4,5,6,7-tetrahydro-indole-lower-alkanoic acids and esters

ABSTRACT

NEW 3-SUBSTITUTED-1 - INDOLE- AND 4,5,6,7 - TETRAHYDROINDOLE-LOWER-ALKANOIC ACIDS AND ESTERS HAVING USEFUL ANTIINFLAMMATORY ACTIVITY AND PREPARED BY ALKYLATION OF A 3 - SUBSTITUTED - INDOLE WITH AN APPROPRIATE HALO-LOWER-ALKANOIC ACID OR ESTER OR BY CYCLIZATION OF A 2-(2-R2-2-OXOETHYL) CYCLOHEXANONE OR 2-(1 -PHENYL-2-OXO-LOWER-ALKYL) CYCLOHEXANONE WITH AN AMINO ACID OR ESTER.

United States Patent 3,557,142 4,5,6,7-TETRAHYDRO-INDOLE-LOWER- ALKANOICACIDS AND ESTERS Malcolm R. Bell, East Greenbush, N.Y., assignor toSterling Drug Inc., New York, N.Y., a corporation of Delaware NoDrawing. Filed Feb. 20, 1968, Ser. No. 706,802 Int. Cl. C07d 27/54 US.Cl. 260326.13 1 Claim ABSTRACT OF THE DISCLOSURE New 3-substituted-1indoleand 4,5,6,7 tetrahydroindole-lower-alkanoic acids and estershaving useful antiinfiammatory activity and prepared by alkylation of a3 substituted indole with an appropriate halo-lower-alkanoic acid orester or by cyclization of a 2-(2-R -2-oxoethyl)cyclohexanone or 2-(1phenyl-2-oxo-lower-alkyl) cyclohexanone with an amino acid or ester.

This invention relates to certain 3-substituted-1-indolelower alkanoicacids and esters having the formula:

-I*R3 N /R2 iK-COORi I r Where R is hydrogen or lower-alkyl; R ishydrogen, lower-alkyl, carboxy, carbo-lower-alkoxy, or hydroxymethyl; Ris phenyl, phenyl lower-alkanoyl, benzoyl, thiophenecarbonyl,furancarbonyl, pyridinecarbonyl, isoxazolecarbonyl, thiazolecarbonyl,phenyl-lower-alkyl, 3-phenyl-3-oxo-1-propenyl, or phenyllower-alkenoyl',and Y is lower-alkylene.

The invention also embraces the 4,5,6,7 tetrahydro derivatives of thecompounds of the Formula I, and the former are represented by theFormula Ia:

| YCOOR1 The compounds of Formulas I and Ia are useful asantiinflammatory agents as more fully discussed hereinafter.

As used herein, the term lower-alkyl means saturated, monovalentaliphatic radicals, including straight or branched-chain radicals offrom one to six carbon atoms, as illustrated by, but not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, amyl, hexyl, and thelike.

As used herein the term lower-alkylene means divalent, saturated,aliphatic radicals, including straight or branched-chain radicals offrom one to six carbon atoms, as illustrated by, but not limited to,methylene, 1,1-ethylene, l,2-ethylene, 1,3-propylene, l,2-propylene,1,6-hexylene, and the like.

As used herein the term phenyl-lower-alkanoyl means a monovalent radicalderived from a phenyl-lower-alkanoic acid by removal of the hydroxylgroup from'the carboxylic moiety thereof. The term thus includesstraight or branched-chain lower-alkanoyl radicals containing from oneto six carbon atoms in the lower-alkanyl moiety. The termphenyl-lower-alkanoyl therefore includes, inter alia, phenylacetyl, 5phenylpropionyl, aphenylpropionyl, y-phenylbutyryl, and the like.

As used herein the term phenyl-lower-alkenoyl" meansisothiazolecarbonyl,

a monovalent radical derived from a phenyl-lower-alkenoic acid byremoval of the hydroxyl group from the carboxylic moiety thereof. Theterm phenyl-lower-alkenoyl includes straight or branched-chainlower-alkenoyl radicals containing from three to six carbon atoms in thelower-alkenoyl moiety, and thus includes, inter alia, cinnamoyl,a-methlycinnamoyl, fi-ethylcinnamoyl, and the like.

The compounds of Formula I are prepared by reaction of an appropriate3-substituted-indole with a halo-loweralkanoic acid or lower-alkyl esterthereof in the presence of an acid-interceptor which serves to take upthe hydrogen halide split out duringthe course of the reaction. Thereaction is represented by the equation:

where R R R and Y have the meanings given above, and X representshalogen. The reaction is carried out at a temperature from 20 C. toabout C. in an organic solvent inert under the conditions of thereaction, for example benzene, toluene, xylene, dimethylformamide, andthe like. A preferred solvent is dimethylformamide, and a preferredacid-acceptor is sodium hydride.

The compounds of Formula I where R is hydrogen can also be prepared bysaponification of the corresponding esters where R is lower-alkyl byheating a solution of the latter in a lower-alkanol, for example,methanol, ethanol, isopropanol, and the like, and containing a molarexcess of an alkali metal hydroxide, for example sodium or potassiumhydroxide.

The compounds of Formula I where R is hydroxymethyl are prepared byreducing the corresponding indole-2-carboxylic acids or esters (R iscarboxy or carbolower-alkoxy) of Formula II with lithium aluminumhydride thus aflording the corresponding compounds of Formula II where Ris hydroxymethyl which are then reacted with a halo-lower-alkanoic acidor lower-alkyl ester thereof, as described above, to give the compoundsof Formula I. The reduction with lithium aluminum hydride is carried outat a temperature from 10 C. to about 70 C. in an organic solvent inertunder the conditions of the reaction, for example diethyl ether ortetrahydrofnran. A preferred solvent is tetrahydrofuran.

The intermediate 3-substituted-indoles of Formula II where R is phenylare prepared by Fischer indole cyclization of an R -benzy1 ketone (oraldehyde) phenyl hydrazone accordng to the reaction:

-Phenyl CH -Phenyl I III II where R has the meanings given above. Thereaction is carried out by heating the hydrazone III in the presence ofan acid, for example hydrochloric acid, sulfuric acid, p-toluenesulfonicacid, glacial acetic acid, and the like, in an organic solvent inertunder the conditions of the reaction, for example methanol, ethanol,isopropanol, benzene, toluene, and the like. When glacial acetic acid isused as the acid condensing agent, it can be used as the solvent mediumas well.

The hydrazones of Formula III in turn are prepared by reacting aphenyihydrazine of Formula IV with an appropriate R -benzy1 ketone (oraldehyde) of Formula V. The reaction is represented by the equation:

H2Pheny1 III NHNHz O: O

IV V

and generally takes place at room temperature. Like the cyclization ofthe hydrazones of Formula III to the indoles of Formula II, the reactionis advantageously carried out in an organic solvent inert under theconditions of the reaction, for example methanol, ethanol, isopropanol,and the like, and in the presence of an acid, for example hydrochloricacid, sulfuric acid, p-toluenesulfonic acid, glacial acetic acid, andthe like.

The hydrazones of Formula III thus formed can, if desired, be isolatedfrom the reaction mixture before cyclizing to the indoles of Formula II,but it is preferred to carry the reaction to completion, withoutisolating the intermediate hydrazones, by heating the reaction mixturecontaining the hydrazone which itself is formed at lower temperatures.

The intermediate 3-substituted-indoles of Formula II where R isbenzoyl,, thiophenecarbonyl, furancarbonyl, pyridinecarbonyl,isoxazolecarbonyl, thiazolecarbonyl, isothiazolecarbonyl,phenyl-lower-alkanoyl, or phenyllower-alke-noyl are prepared by reactingthe acid halide corresponding to the acids defined by the foregoing Rgroups with an appropriate indole magnesium halide which is prepared byreaction of an appropriate indole with a lower-alkyl magnesium halide.The reaction is represented by the equation:

AsX 1/ where R and R have the meanings given above, R representslower-alkyl, and X represents halogen. The reaction is carried out at atemperature from 20 C. to about 100 C. in an organic solvent inert underthe conditions of the reaction, for example diethyl ether,tetrahydrofuran, dioxane, and the like.

The II where R is phenyl-lower-alkyl are prepared by reducing, with analkali metal aluminum hydride, the corresponding compounds where R, isbenzoyl or phenyllower-alkanoyl. The reaction takes place attemperatures in the range from about 20 C. to about 80 C. in an organicsolvent inert under the conditions of the reaction, for example diethylether or tetrahydrofuran. It is preferred to carry out the reaction intetrahydrofuran at the boiling point thereof.

The intermediate 3-substituted-indoles of Formula II where R is3-phenyl-3-oxopropenyl are prepared by reaction of a 2-R-3-indolecarboxaldehyde with a loweralkyl a-benzoylacetate in thepresence of I basic catalyst under aldol condensation conditions, andsaponification and decarboxylation of the resulting 2-R -3-(3-pheny1-3-ox0-2-carbo-lower-alkoxypropenyl)indole. Suitable basic catalysts arepyridine, alkali metal alkoxides, or trilower-alkylam-ines. The reactionis preferably carried out in an organic solvent inert under theconditions of the recation, for example pyridine or lower-alkanols.

intermediate 3-substituted-indoles of Formula The method is representedby the equations:

CHO OHr-CO-Phenyl OOO-Alk N I OH=C O-Phonyl C O OAlk H CH=CHC-Phenyl [R2N whe're R R R and Y have the meanings given above.

The compounds of Formula Ia where R is loweralkyl and R is phenyl areprepared by reaction of a 2- 1-phenyl-2-oxo-lower-alkyl) cyclohexanonehaving the formula:

with an amino acid having the formula H NY-C0OR where R is hydrogen, Ris lower-alkyl, and R is phenyl. The reaction is carried out in anacidic medium, for example glacial acetic acid.

The 2-(1-pheny1-2-oxo-lower-alkyl)cyclohexanones are prepared by themethod of Baumgartner et al., J. Am. Chem. Soc., 80, 6611 (1958) byreacting cyclohexanonepyrrolidine enamine with an appropriateOL-bI'OmO-OC- phenylacetone and hydrolyzing the resulting enaminehaloketone adduct.

The compounds of Formulas I and Ia where R is hydrogen areinter-convertible with the compounds where R is lower-alkyl, andmoreover the acids are interconvertible with salts, for example alkalimetal or alkaline earth salts, or ammonium or amine salts, e.g.-N-methylglucamine, and the salts are considered to be the fullequivalents of the acids and esters here-claimed. Thus the acids (R ishydrogen) are prepared from the esters (R is lower-alkyl) bysaponification of the latter with alkali. The salts are obtained fromthe corresponding acids by reaction of the later with one molarequivalent of an appropriate base, for example an alkali metalhydroxide, alkaline earth hydroxide, ammonia or an amine, and isolationof the product from a neutral or basic medium. The loWer-alkyl esters (Ris lower-alkyl) are obtained from the corresponding acids byesterification of the latter with a lower-alkanol in the presence of amineral acid.

In addition to the use as starting materials or reactants of the indolesof Formula II or R -benzyl ketone (or aldehyde) phenylhydrazones ofFormula III, or benzoyl halides, or phenyl-lower-alkanoyl halides, orphenyllower alkenoyl halides unsubstituted in the benzenoid ringsthereof, other equivalently functioning reactants may be employed toproduce the desired novel compositions of this invention. For example,instead of employing 3-substituted-indoles of Formula II unsubstitutedin the benzenoid ring, or R -benzyl ketone (or aldehyde)phenylhydrazones of Formula III, or benzoyl halides, orphenyllower-alkanoyl halides, or phenyl-lower-alkenoyl halidesunsubstituted in the phenyl ring thereof, such compounds substituted inthe benzenoid or phenyl rings by one or more members of the groupconsisting of halogen (including fluorine, chlorine, bromine, andiodine), loweralkyl, loWer-alkoxy, lower-alkylmercapto, lower-alkyLsulfinyl, lower-alkylsulfonyl, nitro, amino, lower-alkanoylamino,di-lower-alkylamino, trifluoromethyl, methylenedioxy, ethylenedioxy,lower-alkanoyloxy, and hydroxy can also be employed. In such instances,the same reaction conditions used in the previously described reactionscan be used, and such substituted reactants afford the correspondinglysubstituted final products of Formula I which are considered to be thefull equivalents of the unsubstituted compounds herein claimed, asillustrated by the following equations:

l I! ll where R R X, and Y have the meanings given above, and R or thebenzenoid substituent on the phenyl ring of R is phenyl,phenyl-lower-alkanoyl, benzoyl, phenylloWer-alkyl,phenyl-lower-alkenoyl, or 3-pheny1-3-oxopropenyl are each from one tofour substituents selected from the group consisting of halogen,lower-alkyl, loweralkoxy, lower-alkylmercapto, lower-alkylsulfinyl,loweralkylsulfonyl, nitro, amino, lower-alkanoylamino,dilower-alkylamino, trifluoromethyl, methylenedioxy, ethylenedioxy,lower-alkanoyloxy, and hydroxy.

The compounds of Formulas I and II are anti-inflamatory agents asdetermined in standard and recognized pharmacological tests as describedhereinbelow.

Anti-inflammatory activity of the compounds was determined by theinhibition of carrageenin-induced local foot edema in fasted ratsgenerally by the method described by Winter et al., Proc. Soc. Exp.Biol. Med., 111, 544 (1962). The tests were carried out in maleSprague-Dawley rats weighing approximately 10 0 to 115 grams from whichall food was withdrawn twenty-four hours prior to medication. The ratswere divided into groups of at least five rats per group, andsuspensions of the compounds in gum tragacanth were administered bystomach tube in a volume of 1 ml. per g. of body weight. A control groupof animals received only the gum tragacanth. This treatment was followedone hour later by injection into the plantar tissue of the right hindpaw of all test and control animals of 0.05 ml. of a 1% aqueoussuspension of carrageenin. As a control, the left hind paw was similarlyinjected with saline. Swelling of the carrageenin-injected paw reached apeak in from three to five hours, and the increase in swelling threehours after injection of the carrageenin was adopted as a measure ofeffect. Three hours following carrageenin injection the rats weresacrificed and the hind paws were cut off at the tibio-calcaneo-talarjoint and weighed on a Mettler H5 balance. The weight diflerence betweenthe carrageenin-injected foot and the salineinjected foot was taken asthe weight of edema. The difference between the average weights of edemaof the medicated and the control, or unmedicated, groups was expressedas percent inhibition of carrageenin-induced edema by the administeredtest compound. The results were expressed either in terms of the percentinhibition at a dose of 100 mg./kg. or in terms of the AED the AverageEffective Dose producing 40% inhibition of the inflammation, the lattervalue being calculated from a dose-response curve. The compounds werethus found to have an AED in the range from 17 to mg./ kg. Thetoxicities of the compounds, expressed in terms of the ApproximateLethal Dose (ALD determined on oral administration in rats, were foundto be in the range from 800 to 1000 mg./kg.

Although the compounds are less active on a weight-toweight basis thanthe known anti-inflammatory agent, [1r(4-chlorobenzoyl)-5-methoxy 2methyl 3 indole] acetic acid (indomethacin), they are relatively lesstoxic, i.e. have a more favorable ratio of the toxic to the active dose.

The compounds can be prepared for use by dissolving or suspending themin aqueous alcohol, glycol or oil solution, or oil-in water emulsions inthe same manner as conventional medicinal substances are prepared.Alternatively, they can be incorporated in unit dosage form as tabletsor capsules for oral administration either alone or in combination withsuitable adjuvants such as calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia, and the like. The compounds areadministered to any suitable mammalian host in a does range of 2l00 mg./kg.

The chemical structures of the compounds of the invention areestablished by their mode of synthesis and are corroborated by infraredand ultraviolet spectra and by the correspondence between calculatedvalues for the elements and values found by chemical analysis.

The following examples will further illustrate specific embodimentswithout the invention being limited thereto. The melting points areuncorrected.

EXAMPLE 1 (A) 3-benzoylindole [11: R is H; R is C H CO; R is H] .--To asolution of 160 ml. of a 3 M ether solution of ethyl magnesium bromidediluted with 100 ml. of absolute ether was added with stirring, over aperiod of fortyfi've minutes, a solution of 50 g. (0.43 mole) of indolein 300 ml. of absolute ether while maintaining the temperature at 0-5 C.The resulting yellow suspension was allowed to warm to C. for thirtyminutes and was then cooled to 05 C. and treated with a solution of 60g. (0.43 mole) of benzoyl chloride in 90 ml. of absolute ether. Themixture was then refluxed for two and one-half hours, allowed to standat room temperature overnight, treated with 400 ml. of saturated aqueousammonium chloride, and the ether-soluble product was extracted with 1500ml. of tetrahydrofuran. The extracts were dried over anhydrous sodiumsulfate and evaporated to dryness in vacuo to give a light pink solidwhich was recrystallized from ethyl acetate giving 50 g. of3-benzoylindole, M.P. 237239 C.

(B) Ethyl a-(3-benzoyl-1-indole)acetate [1: R is C H R is H; R is C HCO; R is H; Y is CH ].A mixture of g. (0.09 mole) of 3-benzoylindole and5.1 g. (0.11 mole) of a 52% suspension of sodium hydride in mineral oilin 250 ml. of dry dirnethylformamide was stirred at room temperature forforty-five minutes. The resulting orange, almost clear solution wastreated all at once with 17.9 g. (0.11 mole) of ethyl bromoacetate, andthe resulting solution was stirred for two hours and then allowed tostand for six hours. The clear, red-brown solution was diluted with 2liters of ethyl acetate, washed with three 500 ml. portions of water,once with saturated brine, dried over anhydrous sodium sulfate andevaporated to dryness in vacuo to give 30.2 g. of ethyla-(3-benzoyl-l-indole)- acetate.

(C) a-(3-benzoyl-1-indole)acetic acid [I: R and R are H; R is C H CO; Ris H; Y is CH .A solution of 30.2 g. (0.10 mole) of ethyla-(3-benzoyl-l-indole)acetate in 400 ml. of ethanol and 105 ml. of 10%aqueous sodium hydroxide was refluxed for two hours, and the solventremoved by evaporation in vacuo. The residual yellow gum was dissolvedin two liters of ethanol/water and the solution acidified to pH 1 with33% hydrochloric acid. The fiocculent precipitate was collected, dried,and recrystallized twice from ethanol to give 18.1 g. of (It-(3-benzoyl-l-indole)acetic acid, M.P. 2l6-2l8 C.

Analysis.-Calcd. for C H NO (percent): C, 73.11; H, 4.69; N, 5.03. Found(percent): C, 73.34; H, 4.82; N, 5.15.

EXAMPLE 2 (A) 3-benzoyl-2-methylindole [11: R is CH R is C H CO; R is H]was prepared by reaction of 103 g. (0.73 mole) of benzoyl chloride withthe Grignard reagent prepared from 96 g. (0.73 mole) of Z-methylindoleand 275 ml. (0.82 mole) of a 3 M ether solution of ethyl magnesiumbromide in a total volume of about 950 ml. of diethyl ether using theprocedure described above in Example 1(A). The crude product wasrecrystallized from ethyl acetate to give 93.5 g. of3-benzoyl-2-methylindole, M.P. 183184 C.

(B) Ethyl a-(3-benzoyl-2-rnethyl-l-indole)acetate [I1 R is C H R is CH Ris C H CO; R is H; Y is CH was prepared by reacting 20.0 g. (0.085 mole)of 3-benzoyl-2-methylindole with 17.0 g. (0.10 mole) of ethylbromoacetate in 250 ml. of dry dimethylformamide in the presence of 4.85g. (0.103 mole) of a 52% suspension of sodium hydride in mineral oilusing the procedure described above in Example 1(B). There was thusobtained 35.2 g. of ethyl a-(3-benzoyl-2-methyl-l-indole)acetate as abrown oil.

(C) a-(3-benzoyl-2-methyl-I-indole)acetatic acid [I: R is H; R is CH Ris C H CO; R is H; Y is CH was prepared by saponification of 35.2 g.(0.11 mole) of ethyl a-(3-benzoyl-2-methyl-1-indole)acetate in asolution of 400 ml. of ethanol and ml. of 10% aqueous sodium hydroxideusing the procedure described above in Example 1(C). The crude productwas recrystallized twice from ethanol to give 13.2 g. ofa-(3-benzoyl-2-methyl-l-indole) acetic acid, M.P. 211212 C.

Analysis.Calcd. for C H NO (percent): C, 73.70; H, 5.15; N, 4.78. Found(percent): C, 74.85; H, 5.24; N, 5.07.

EXAMPLE 3 (A) Ethyl B-(3-benzoyl-2-methyl-1-indole)propionate [II R1 isC2H5; R2 is R3 is R4 is Y is CH CH was prepared by reacting 20.0 g.(0.085 mole) of 3-benzoyl-2-methylindole with 18.5 g. (0.102 mole) ofethyl B-bromo-propionate in 250 ml. of dry dimethylformamide in thepresence of 4.8 g. (0.103 mole) of a 52% suspension of sodium hydride inmineral oil using the procedure described above in Example 1(B). Therewas thus obtained 34.0 g. of ethyl fl-(3-benzoyl-2-methyl-l-indole)propionate as a brown oil.

(B) 5-(3-benzoyl-2-methyl-l-indole)propionic acid [I: R1 is R2 is R3 isR4 is Y is was prepared by saponification of 34.0 g. (0.10 mole) ofethyl ,B-(3-benzoyl-2-methyl-1-indole)propionate in a solution of 400ml. of ethanol and 100 ml. of 10% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized twice from ethanol to give 13.5 g. of ,8-(3-benzoyl-2-methyl-l-indole)propionic acid, M.P. 205 207 C.

Analysis.-Calcd. for C H NO (percent): C, 74.25; H, 5.58; N, 4.56. Found(percent): C, 74.85; H, 5.80; N, 5.07.

EXAMPLE 4 (A) 3-(4-chlorobenzoy1)indole [II: R is H; R, is 4-ClC H CO; Ris H] was prepared by reaction of 74.0 g. (0.43 mole) of 4-chlorobenz0ylchloride with the Grignard reagent prepared from 50.0 g. (0.43 mole) ofindole and ml. (0.49 mole) of a 3 M ether solution of ethyl magnesiumbromide in a total volume of about 450 ml. of diethyl ether using theprocedure described above in EX- ample 1(A). The crude product wasrecrystallized from ethyl acetate to give 52.6 g. of3-(4-chlorobenzoyl)indole M.P. 200 C.

(B) Ethyl a-[3-(4-chlorobenzoyl)-l-indole]acetate [1: R1 is C2H5; R2 isR3 is R4 is Y is was prepared by reaction of 15.7 g. (0.94 mole) ofethyl bromoacetate with 20.0 g. (0.078 mole) of3-(4-chlorobenzoyl)-indole in 250 ml. of anhydrous dimethylformamide inthe presence of 4.5 g. (0.094 mole) of a 50% suspension of sodiumhydride in mineral oil using the procedure described above in Example1(B). There was thus obtained 31.7 g. of ethyl a-[3-(4-chlorobenzoyl)-1-indole]actate as an off-white solid.

(C) u-[3-(4-chlorobenzoyl)-l-indole]acetic acid [1: R and R are H; R is4-ClC H CO; R is H; Y is CH was prepared by saponification of 31.7 g.(0.093 mole) of ethyl a-[3-(4-chlor0benzoyl)-1-ind0le] acetate in asolution of 400 ml. of ethanol and 100 m1. of 10% aqueous sodiumhydroxide using the procedure described above in Example 1(C). The crudeproduct was recrystallized once from ethanol/benzene and once fromethanol to give 13.6 g. of a-[3-(4-chlorobenzoyl)-1-indole]acetic acid,M.P. 235236 C.

Analysis.-Calcd. for C H ClNO (percent): N, 4.47; Cl, 11.30. Found(percent): N, 4.72; C1, 11.09.

9 EXAMPLE (A) 3-(4-chlorobenzoyl)-2-methylindole [IIz R is CH R is 4-ClCH CO; R is H] was prepared by reaction of 133.5 g. (0.96 mole) of4-chlorobenzoy1 chloride with the Grignard reagent prepared from 100 g.(0.70 mole) of 2-methylindole and 300 ml. (0.90 mole) of a 3 M ethersolution of ethyl magnesium bromide in a total volume of about 1100 ml.of absolute diethyl ether using the procedure described above in Example1(A). The crude product was recrystallized from ethyl acetate to give157 g. of 3-(4-chlorobenzoyl)-2-methylindole, M.P. l8ll83 C.

(B) Ethyl a-[3-(4-chlorobenzoyl)-2-methyl-1-indole] acetate [1: R is C HR is CH R is 4-ClC H CO; R is H; Y is CH was prepared by reaction of74.3 (0.45 mole) of ethyl bromoacetate with 100 g. (0.37 mole) of3-(4-chlorobenzoyl)-2-rnethylindole in one liter of anhydrousdimethylformamide in the presence of 21.0 g. (0.46 mole) of a 52%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained 146.4 g. ofcrude product as a peach colored solid of which 25 g. was recrystallizedfrom ethanol to give 15.1 g. of ethyl a-[3-(4-chlorobenzoyl)-2-methyl-1-indole]acetate as a white, peach-tinted solid, M.P. 145-146 C.

Aalysis.Calcd. for C H ClNO (percent): C, 67.51; H, 5.10; N, 3.94; Cl,9.97. Found (percent): C, 67.74; H, 5.19; N, 3.93; Cl, 9.84.

(C) ot- [3- (4-chlorobenzoyl) -2-methyl-1-indole] acetic acid [I: R isH; R is CH R is 4-ClC H CO; R is H; Y is CH was prepared bysaponification of 39 g. (0.11 mole) of ethyla-[3-(4-chlorobenzoyl)-2-methyl-1-indole] acetate in a solution of 800ml. of ethanol and 200 ml. of aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized twice from ethanol and dried in vacuo at 100 C. to give10.6 g. of a-[3-(4-chlorobenzoy1)-2-methyl-l-indole] acetate acid, M.P.233-236 C.

Analysis.Calcd. for C H ClNO (percent): C, 65.95; H, 4.30; N, 4.27; Cl,10.82. Found (percent): C, 65.70; H, 4.48; N, 4.62; Cl, 11.05.

EXAMPLE 6 (A) 'Ethyl B-[3-(4-chlorobenzoyl)-2-methyl-1-indole]propionate [I: R is C H R is CH R is 4-CIC H CO; R is H; Y is CH CH wasprepared by reaction of 20.8 g. (0.115 mole) of ethyl fi-bromopropionatewith 28 g. (0.104 mole) of 3-(4-chlorobenzoyl)-2-methylindole in thepresence of 5.3 g. (0.12 mole) of a 52% suspension of sodium hydride inmineral oil in a total of 250 ml. of dimethylformamide using theprocedure described above in Example 1(B). There was thus obtained 36 g.of ethyl fl-[3-(4-chlorobenzoyl)-2-methyl-1-indole]propionate as ayellow, viscous oil.

(B) ;9- [3-(4-chlorobenzoyl)-2-methyl-1-indo1e]propionic acid [1: R isH; R is CH R is 4-CIC H CO; R is H; Y is CH CH was prepared bysaponification of 36 g. (0.098 mole) of ethyl5-[3-(4-chlorobenzoyl)-2-methyl- 1-indole]propionate in a solution of800 ml. of ethanol and 200 ml. of 10% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized twice from tetrahydrofuran to give 11.0 g. of,8-[3-(4-chlorobenzoyl)-2-methyl-1-indole] propionic acid, M.P. 224-227C. (dec.).

Analysis.Calcd. for C H -ClNO (percent): N, 4.10; C], 10.37. Found(percent): N, 4.34; Cl, 10.48.

EXAMPLE 7 (A) 3-(3,4-dichlorobenzoyl)-2-methylindole [11: R is CH R is3,4-Cl C H CO; R is H] was prepared by reaction of 100 g. (0.48 mole) of3,4-dichlorobenzoyl chloride with the Grignard reagent prepared from62.5 g. (0.48 mole) of 2-methylindole and 191 ml. (0.57 mole) of anapproximately 3 M ether solution of methyl magnesium bromide in a totalof 800 ml. of anhydrous 10 diethyl ether using the procedure describedabove in Example 1(A). There was thus obtained 20.8 g. of 3-(3,4-dichlorobenzoyl)-2-methylindole, M.P. 229-230 C.

Analysis.Calcd. for C H Cl NO (percent): C, 63.17; H, 3.64; N, 4.60; Cl,23.32. Found (percent): C, 62.95; H, 3.45; N, 4.46; Cl, 23.09.

3-(3,4-dichlorobenzoyl)-2-methylindole was studied in electrolyteexcretion modification tests in rats, and found to be active as akaluretic agent at a dose of 30 mg./kg. (s.c.). The test for electrolyteexcretion modification .was carried out as follows: Male Charles RiverCD rats weighing 180 to 195 g. were maintained in the laboratory for oneweek to equilibrate them, during which time water and food were providedad libitum. All food was removed from the cages of the test animalsapproxi m-ately eighteen hours preceding the test, and water was removedtwo and one-half hours preceding the test. All test animals were thenvoided of urine by applying pressure with the fingers over the region ofthe bladder, and after weighing, were divided into experimental groupsand placed into individual metabolism cages equipped for urinecollection. All rats were then administered intraperitoneally 10 ml. ofKrebs Ringer phosphate solution, and the test compound, prepared as asuspension in 10% ethanol-cottonseed oil, was injected subcutaneouslyimmediately following administration of the Krebs Ringer solution. Asecond and third injection of the test compound were administered twoand four hours later, care being taken at all times to prevent urineloss by holding the animal over the collection funnel while injecting.Twenty-four hours following the injection of the Krebs Ringer solution,the animals were again voided of urine while being held over thecollection funnel. The animals were then sacrificed by injection ofpentobarbital prior to final weighing. Urine volumes were recorded ineach case, and the metabolism cages were washed down with small amountsof distilled water, and the urine samples with the water washings werediluted to ml. with distilled water. Suitable aliquots were thenanalyzed for sodium, potassium, chloride, magnesium, phosphorus,calcium, and nitrogen by standard analytical procedures.

,(B) Ethyl a [3-(3,4-dichlorobenzoyl)-2-methyl-1-indole]acetate [1: R isC H R is CH R is 3,4- Cl C H CO; R is H; Y is CH was prepared byreaction of 23.0 g. (0.14 mole) of ethyl bromoacetate with 35.0 g. (0.12mole) of 3-(3,4-dichlorobenzoyl)-2- methylindole in 250 ml. of anhydrousdimethylformamide and in the presence of 5.92 g. (0.138 mole) of a 56%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained 48 g. of ethyla-[3,4-dichlorobenzoyl)-2- methyl-1-indole]acetate as a yellow oil.

(C) o: [3-(3,4-dichlorobenzoyl)-2-methyl-1-ind0le] acetic acid [I: R isH; R is CH R is 3,4-Cl C H CO; R is H; Y is CH was prepared bysaponification of 48 g. (0.12 mole) of ethyla-[3-,(3,4-dichlorobenzoyl)-2- methyl-1-indole]acetate in a solution of500 ml. of ethanol and ml. of 10% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized three times from ethanol giving 19.5 g. ofu-[3-(3,4-dichlorobenzoyl)-2- methyl-1-indole]acetic acid, M.P. 212 214C.

Analysis.-Calcd. for C H CI NO (percent): C, 59.68; H, 3.61; N, 3.87.Found (percent): C, 59.72; H, 3.70; N, 3.63.

EXAMPLE 8 11 145-170 C. consisting of 1,3-di-(4-chlorobenzoyl)-6-methoxy-Z-methylindole, was dissolved in ethanol and benzene and warmedgently with a solution of 6 g. of sodium hydroxide in 50 ml. of H tohydrolyze oil the l-(4-chlorobenzoyl) group introduced during thereaction. The product was recrystallized from benzene to give 34-chlorobenzoyl -6-methoxy-2-methylindole as pale yellow, microcrystals, M.P. 206208.5 C.

Analysis.-Calcd. for C H CINO (percent): C,

68.11; H, 4.71; Cl, 11.83; N, 4.68. Found (percent): C, 68.68; H, 4.74;Cl, 11.67; N, 4.70.

(B) Ethyl a-[3-,(4-chlorobenzoyl)-6-methoxy-2-methyl-l-indole]acetate[I1 R is C H R is CH R is 4-ClC H CO; R is 6-CH O; Y is CH was preparedby reaction of 1.39 g. (0.019 mole) of ethyl brornoacetate with 5.2 g.(0.017 mole) of 3-(4-chlorobenzoyl)- 6-methoXy-24methylindole in thepresence of 0.88 g. (0.019 mole) of a 52% suspension of sodium hydridein mineral oil in 50 ml. of dimethylformamide using the proceduredescribed above in Example 1(B). There was thus obtained 6 g. of ethyla-[3-(4-chlorobenzoyl)-6- methoxy-Z-methyl-l-indole]acetate as a lightbrown gum.

(C) or [3-(4-chlorobenzoyl)-6-methoxy-2-methyl-1- indole]acetie acid [I:R is H; R is CH R is 4- ClC H CO; R is 6-CH O; Y is CH was prepared bysaponification of 6 g. (0.016 mole) of ethyl a-[3-(4- chlorobenzoyl-6-methoxy-2-methyl- 1 -indole] acetate in a solution of 400 ml. ofethanol and 50 ml, of 10% aqueous sodium hydroxide using the proceduredescribed above in Example 1(C). The crude product was recrystallizedfrom ethanol to give 4.0 g. ofa-[3-(4-chlorobenzoyl)-6-methoxy-2-methy1-l-indole]acetic acid, M.P.230.5234 C.

Analysis.-Calcd. for C H ClNO (percent): C, 63.78; H, 4.51; CI, 9.91.Found (percent): C, 63.68; H, 4.58; Cl, 10.19.

EXAMPLE 9 (A) 3 (4-methylbenzoyl)-2-methylindole [Hz R is CH R is 4-CH CH CO; R is H] was prepared by reaction of 59 g. (0.38 mole) of4-methylbenzoyl chloride with the Grignard reagent prepared from 50 g.(0.38 mole) of 2-rnethylindole and 140 ml. (0.42 mole) of a 3 M ethersolution of ethyl magnesium bromide in a total of about 550 ml. ofabsolute diethyl ether using the procedure described above in Example1(A). The crude product was recrystallized from ethyl acetate to give 67g. of 3-(4-rnethylbenzoyl)-2-methyl-indole, M.P. 202-204.5 C.

(B) Ethyl ot-[3-(4-methylbenzoyl)-2-methyl-1-indole] acetate [Iz R is CH R is CH R is 4-CH C H CO; R., is H; Y is CH was prepared by reactionof 23.4 g. (0.14 mole) of ethyl bromoacetate with 32 g. (0.13 mole) of3-(4-methylbenzoyl)-2methylindole in the presence of 5.4- g. (0.14 mole)of a 62% suspension of sodium hydride in mineral oil in 250 ml. ofdimethylformamide using the procedure described above in Example 1(B).There was thus obtained 62 g. of ethyl a-[3-)4-methylbenzoyl)2-methyl-1-indole]acetate as a yellow solid.

(C) a [3-(4-methylbenzoyl)-2-rnethyl-1-indole]acetic acid [I2 R is H; Ris CH R is 4-CH C H CO; R is H; Y is CH was prepared by saponificationof 62 g. (0.19 mole) of ethyla-[3-(4-methylbenzoyl)-2-methyl-1-indole]acetate in a solution of 450ml. of ethanol and 125 ml. of 35% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized three times from ethanol to give 21.5 g. ofa-[3-(4-methylbenzoyl)-2-methyl-1-indole]acetic acid, M.P. 226-2295 c.(dec.).

Analysis.-Calcd. for C H NO (percent): C, 74.25; H, 5.58; N, 4.56. Found(percent): C, 74.52; H, 5.68; N, 4.57.

EXAMPLE 10 (A) 3-(4-methoxybenzoyl)-2-methylindole [II: R is CH R is4-CH OC H CO; R is H] was prepared by reaction of 75.9 g. (0.45 mole) of4-methoxybenzoyl chloride with the Grignard reagent prepared from 50 g.(0.38 mole) of Z-methylindole and ml. (0.45 mole) of a 3 M ethersolution of ethyl magnesium bromide in a total of about 550 ml. ofabsolute ether using the procedure described above in Example 1(A).There was thus obtained 111.4 g. of 3-(4-methoxybenzoyl)-2-methylindole.

(B) Ethyl a [3 (4-methoxybenzoyl)-2-mcthyl-1-indole]acetate [I: R, is CH R is CH R is R is H; Y is CH was prepared by reaction of 18.9 g.(0.113 mole) of ethyl bromoacetate with 25 g. (0.09 mole) of3-(4-methoxybenzoyl)-2-methylindole in the presence of 5.3 g. (0.11mole) of a 52% suspension of sodium hydride in mineral oil in 250 ml. ofanhydrous dimethylformamide using the procedure described above inExample 1(B). There was thus obtained 41 g. of ethyl or-[3-(4-methoxybenzoyl)-2-methyl-1-indole]acetate as a red oil.

(C) oz [3 (4-methoxybenzoyl)-2-methyl-l-indole] acetic acid [I: R is H;R is CH R is 4-CH OC H CO; R is H; Y is CH was prepared bysaponification of 41 g. (0.12 mole) of ethyl u-[3-(4-methoxybenzoyl)-2-methyl-1-indole1acetate in a solution of 400 ml. of ethanol and 100 ml.of 10% aqueous sodium hydroxide using the procedure described above inExample 1(C). The crude product was recrystallized twice from ethanol togive 16.0 g. of a-[-3-(4-methoxybenzoyl)-2-methyl-1-indole] acetic acid,M.P. 208-210 C.

Analysis.Calcd. for C19H17NO4 (percent): C, 70.57; H, 5.30; N, 4.33.Found (percent): C, 70.74; H, 5.33; N, 4.69.

EXAMPLE 11 (A) 3-(4-trifiuoromethylbenzoyl)-2-methylindole [II: R is CHR is 4-CF C H CO; R is H] was prepared by reaction of 50.0 g. (0.24mole) of 4-trifluoromethylbenzoyl chloride with the Grignard reagentprepared by reacting 32.2 g. (0.24 mole) of 2-rnethylindole with 100 ml.(0.30 mole) of a 3 M ether solution of methyl magnesium bromide in atotal volume of about 375 ml. of absolute diethyl ether using theprocedure described above in Example 1(A). The crude product wasrecrystallized twice from ethyl acetate to give 42 g. of3-(4-trifiuoromethylbenzoyl)-2methylindole M.P. 197 C.

3-(4-trifiuoromethylbenzoyl)-2-methylindole, in standard serial dilutionanti-vacterial tests, was found to be bacteriostatio against theorganism Staphylococcus aureus at a concentration of 0.075 mg./ml.Antibacterial activity was determined using standard serial dilutiontests as described, for example, by Bailey et al., J. Am. Pharm. Assn-.,Sc. Ed. 48, 212 (1959).

(B) Ethyl a [3-(4-trifluoromethylbenzoyl)-2-methyl- 1-ind0le]acetate [1:R is C H R is CH R is R is H; Y is CH was prepared by reaction of 10.95g. (0.099 mole) of ethyl bromoacetate with 25.0 g. (0.083 mole) of3-(4-trifluoromethylbenzoyl)-2-methylindole in the presence of 4.25 g.(0.099 mole) of a 56% suspension of sodium hydride in mineral oil in 500m1. of dimethylformarnide using the procedure described above in Example1(B). The crude product was recrystallized three times from ethanol togive 3.5 g. of ethyla-[3-(4-trifiuoromethylbenzoyl)-2-methyl-1-indole]acetate, M.P. 128- 132C.

Analysis.-Calcd. for C H F NO (percent): C, 64.77; H, 4.66; F, 14.64.Found (percent): C, 64.96; H, 4.43; F. 14.11.

(C) at [3 (4-trifluoromethylbenzoyl)-2-methyl-1-indole] acetic acid [I:R is H; R is CH R is 4-CF C H CO R is H; Y is CH was prepared bysaponification of 28 acetic acid, M.P. 228-231 C. (dec.).

AnaI sis.--Calcd. for C H F NO (percent): C, 63.15; H, 3.90; N, 3.88; F,15.77. Found (percent): C, 63.43; H, 4.05; N, 3.99; F, 15.50.

EXAMPLE 12 (A) Ethyl B-(3-benzoyl-1-indole)propionate [Iz R is C H R isH; R is C H CO; R is H; Y is CH CH was prepared by reacting 19.0 g.(0.086 mole) of 3-benzolindole with 20 g. (0.12 mole) of ethylB-bromopropionate in 250 ml. of dimethylformamide in the presence of 5.0g. of a 52% suspension of sodium hydride in mineral oil using theprocedure described above in Example 1(B). There was thus obtained 27.7g. of ethyl [3-(3-benzoyl-l-indole)propiona-te as a brown oil.

(B) B-(3-benzoyl-1-indole)propionic acid [I: R and R are H; R3 is C HCO; R is H; Y is CH CH was prepared by saponification of 27.7 g. (0.086mole) of ethyl B-(3-benzoyl-1-indole)propionate in 400 ml. of ethanoland 100 ml. of 10% aqueous sodium hydroxide using the proceduredescribed above in Example 1(C). The crude product was recrystallizedtwice from ethanol giving 6.5 g. of ,8-(3-benzoyl-1-indole)-propionicacid, M.P. 190- 193 C.

Analysis.Calcd. for C H NO (percent): C, 73.10; H, 5.15; N, 4.78. Found(percent): C, 73.42; H, 5.14; N, 4.61.

EXAMPLE 13 (A) 3-cinnamoyl-Z-methylindole [11: R is CH R is C H CH=CHCO;R is H] was prepared by reaction of 64 g. (0.38 mole) of cinnamoylchloride in 200 ml. of a 1:1 solution of ethyl ether and tetrahydrofuranwith the Grignard reagent prepared from 50 g. (0.38 mole) ofZ-methylindole and 138 ml. (0.41 mole) of a 3 M ether solution of ethylmagnesium bromide in a total volume of about 350 ml. of absolute etherusing the procedure described above in Example 1(A). The crude productwas recrystallized from ethyl acetate to give 36.5 g. of3-cinnamoyl-2-methylindole, M.P. 153.5156.5 C. resolidifies and melts at166-168 C.).

Analysis.-Calcd. for C H NO (percent): C, 82.73; H, 5.79; N, 5.36. Found(percent): C, 83.06; H, 6.07; N, 5.09.

(B) Ethyl a (3-cinnamoyl-2-methyl-l-indole)acetate [Ii R1 is C2H5; R2 isR3 is R4 iS H; Y is CH was prepared by reacting 16.6 g. (0.062 mole) of3-cinnamoyl=2-methylindole with 11.3 g. 0.068 mole) of ethylbromoacetate in 125 ml. of dry dimethylformamide in the presence of 2.68g. (0.069 mole) of a 62% suspension of sodium hydride in mineral oilusing the procedure described above in Example 1(B). There was thusobtained 20 g. of ethyl a-(3-cinnamoyl-2-methyl- 1-indole)acetate, M.P.110-112 C.

(C) a-(3-cinnamoyl-2-methyl-l-indole)acetic acid [1: R is H; R is CH Ris C H CH=CHCO; R is H; Y is CH was prepared by saponification of 20 g.(0.058 mole) of ethyl a-(3-cinnamoyl-2-methyl-l-indole)acetate in asolution containing g. of potassium hydroxide in 250 ml. of methanolusing the procedure described above in'Example 1(C). The crude productwas recrystallized from ethanol to give 9.6 g. ofa-(3-cinnamoyl-2-methyl- 1-indole)acetic acid, M.P. 220-225 C.

Analysis.-Calcd. for C20H17NO3 (percent): C, 75.22; H, 5.37; N, 4.39.Found (percent): C, 75.52; H, 5.47; N, 4.20.

EXAMPLE 14 (A) Ethyl [3-(3-cinnamoyl-2-methyl-l-indole)propionate [Iz Ris C H R is CH R is C H CH CHCO;

R is H; Y is CH CH was prepared by reacting 14.5 g. (0.056 mole) of3-cinnamoyl-2-methylindole with 11.05 g. (0.061 mole) of ethyl8-bromo-propionate in ml. of dry dimethylformamide in the presence of2.42 g. (0.061 mole) of a 61% suspension of sodium hydride in mineraloil using the procedure described above in Example 1(B). There was thusobtained 20 g. of ethyl ,8-(3-cinnamoyl-2-methyl-l-indole)propionate asa yellow gum.

(B) ,8 (3-cinnamoyl-2-methyl-1-indole)propi0nic acid [I: R is H; R is CHR is C H CH=CHCO; R is H; Y is CH CH was prepared by saponification of20 g. (0.063 mole) of ethyl B-(3-cinnamoyl-2-methyl-l-indole) propionatein a solution containing 30 g. of potassium hydroxide dissolved in 200ml. of methanol using the procedure described above in Example 1(C). Thecrude product was recrystallized from ethanol to give 7.5 g. of ,8-(3-cinnamoyl-Z-methyl-1-indole)propionic acid, M.P. 164- 166 C.(resolidifies and melts 190191 C.).

Analysis.Calcd. for C H NO (percent): C, 75.65; H, 5.74; N, 4.20. Found(percent): C, 75.66; H, 5.66; N, 3.93.

EXAMPLE 15 (A) 3-benzoyl-2-methyl-5,6-dimethoxyindole [II: R; is CH R isC H CO; R is 5,6-(CH O) was prepared by reaction of 14.0 g. (0.1 mole)of benzoyl chloride with the Grignard reagent prepared from 19.1 g. (0.1mole) of 2-methyl-5,6-dimethoxyindole and 37 ml. (0.11 mole) of a 3 Mether solution of ethyl magnesium bromide in a total volume of 150 ml.of tetrahydrofuran using the procedure described above in Example 1(A).The crude product was recrystallized from ethanol giving 6.1 g. of 3benzoyl 2 methyl-5,6-dimethoxyindole, M.P. 210- 212 C.

Analysis.Calcd. for C H NO (percent): C, 73.20; H, 5.80; N, 4.74. Found(percent): C, 73.21; H, 5.82; N, 4.57.

(B) Ethyl u-( 3 benzoyl 2 methyl-5,6-dimethoxy-1- indole)acetate [I2 Ris C H R is CH R is C H CO; R is 5,6-(CH O) Y is CH was prepared byreacting 15 g. (0.051 mole) of 3-benzoyl-2-rnethyl-5,6-dimethoxyindolewith 9.35 g. (0.056 mole) of ethyl bromoacetate in ml. of drydimethylformamide in the presence of 2.23 g. (0.056 mole) of a 61%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained ethyl lit-(3-benzoyl 2 methyl-5,6-dimethoxy-l-indole)acetate as a pale yellow solid.

(C) a (3 benzoyl-2-methyl-5,6-dimeth0xy-l-indole) acetic acid [I: R isH; R is CH R is C H CO; R is 5,6-(CH O) Y is CH was prepared bysaponification of the ethyl a-(3-benzoyl-2-methyl-5,6-dimethoxy-l-indole)acetate described above in Example 15(B), in asolution containing 30 g. of potassium hydroxide in 200 ml. of ethanolusing the procedure described above in Example 1(C). The crude productwas recrystallized from ethanol and dried in vacuo at 100 C. to give11.5 g. of 06-(3- benzoyl 2 methyl-5,6-dimethoxy-1-indole)acetic acid,melts partially at 138-140 C., resolidifies and melts again at 189-190V.

Analysis.-Calcd. for C H NO (percent): C, 67.98; H, 5.58; N, 3.96. Found(percent): C, 66.23; H, 5.58; N, 3.76.

EXAMPLE 16 (A) Ethyl fi-( 3 benzoyl 2 methyl 5,6-dimethoxy-1-indole)-propionate [I1 R is C H R is CH R is C6H5CO; R4 is Y is Wasprepared by reacting 16 g. (0.054 mole) of 3-benzoyl-2-methyl-5,6-dimethoxyindole with 10.3 g. (0.057 mole) of ethylB-bromopropionate in 100 ml. of dry dimethylfol'mamide in the presenceof 2.36 g. (0.06 mole) of a 61% suspension of sodium hydride in mineraloil using the procedure described above in Example 1(B). There 15 wasthus obtained ethylfl-(3-benzoyl-2-methyl-5,6-dimethoxy-l-indole)-propionate as a lightbrown gum.

(B) ,B-(3-benzoyl 2 methyl 5,6 dimethoxy l-indole)propionic acid [1: Ris H; R is CH R is C H CO; R is 5,6-(CH O) Y is CH CH was prepared bysaponification of the ethyl B-(3-benzoyl-2- methyl-5,6-dimethoxy 1indole)propionate obtained above in Example 16(A) in a solutioncontaining 30 g. of potassium hydroxide in 200 ml. of methanol using theprocedure described above in Example 1(C). The crude product wasrecrystallized from ethanol to give 12.7 g. of [3-(3 benzoyl 2 methyl5,6 dimethoxy 1 indole) propionic acid, M.P. 198201 C.

Analysis.-Calcd. for C H NO (percent): C, 68.65; H, 5.76; N, 3.81. Found(percent): C, 68.92; H, 5.87; N, 3.62.

EXAMPLE 17 (A) Ethyl ,B-[3 (4 methylbenzoyl) 2 methyl lindole]propionate[1: R is C H R is CH R is 4-CH C H CO; R is H; Y is CH CH was preparedby reaction of 32 g. (0.13 mole) of 3-(4-methylbenzoyl)2 methylindolewith 25.4 g. (0.14 mole) of ethyl fi-bromopropionate in 250 ml. ofdimethylformamide in the presence of 5.4 g. (0.14 mole) of a 62%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained ethyl fi-[3 (4methylbenzoyl) 2 methyl-l-indole]propiomate as a yellow gum.

(B) ,8-[3 (4 methylbenzoyl) 2 methyl-l-indole] propionic acid [I: R isH; R is CH R is R is H; Y is CH CH was prepared by saponification of theethyl fi-[3 (4-methylbenzoyl)-2-methyl-1-indole] propionate obtainedabove in Example 17(A) in a solution containing 30 g. of potassiumhydroxide in 200 ml. of methanol using the manipulative proceduredescribed above in Example 1(C). The crude product was recrystallizedfrom ethanol giving 19 g. of fl-[3-(4-methylbenzoyD-2-methyl-1-indole]propionic acid, M.P. 210.5-213 C.

Analysis.Calcd. for C H NO (percent): C, 74.74; H, 5.96; N, 4.36. Found(percent): C, 74.57; H, 6.11; N, 4.00.

EXAMPLE 18 (A) 3-(4 chlorobenzoyl) 2 methyl 5,6 dimethoxyindole [II: Ris CH R is 4-ClC H CO; R is 5,6-(CH3O) was prepared by reacting 112 g.(0.64 mole) of 4-chlorobenzoyl chloride with the Grignard reagentprepared from 58 g. (0.30 mole) of 2-methyl-5,6- dimethoxyindole and 11ml. (0.33 mole) of a 3 M ether solution of ethyl magnesium bromide in atotal of 650 ml. of tetrahydrofuran using the procedure described abovein Example 1(A). The crude product was recrystallized from ethanol togive 49 g. of 3-(4-chlorobenz0yl)-2-methyl-5,6-dimethoxyindole, M.P.223.5-225.5 C.

Analysis.Calcd. for C H CINO (percent): C, 65.55; H, 4.89; N, 4.25; Cl,10.75. Found (percent): C, 65.69; H, 4.95; N, 4.00; Cl, 10.71.

(B) Ethyl oz-[3 (4 chlorobenzoyl) 2 methyl-5,6-dimethoxy-l-indole]propionate [I: R is C H R is CH R3 is R4 is5,6-(CH30)2; Y iS Was prepared by reacting 19.5 g. (0.059 mole) of3-(4-chlorobenzoyl) 2 methyl-5,6-dimethoxyindole with 11.2 g. (0.062mole) of ethyl a-bromopropionate in 100 ml. of dry dimethylformamide inthe presence of 2.58 g. (0.065 mole) of a 61% suspension of sodiumhydride in mineral oil using the procedure described above in Example 1(B). There was thus obtained ethyl a-[3-(4-chlorobenzoyl)-2-methyl-5,6-dirnethoxy-1-indole]propionate.

(C) oc-[3 (4 chlorobenzoyl) 2 methyl 5,6 dimethoxy 1 indole]propionicacid [I: R is H; R is CH R is 4-ClC H CO; R is 5,6-(CH O) Y is CH CH]was prepared by saponification of the ethyl lit-[3 (4 chlorobenzoyl) 2methyl 5,6 dimethoxy- 1-indole]propionate obtained above in Example18(8) in a solution containing 35 g. of potassium hydrxide in 250 ml. ofmethanol using the procedure described above in Example 1(C). The crudeproduct was recrystallized once from ethanol and once from ethyl acetateto give 13.5 g. of OL-[3 (4 chlorobenzoyl) 2 methyl-5,6-dimethoxy-1-indole]propionic acid, M.P. 174176.5 C.

EXAMPLE 19 (A) Ethyl OL-[3 (4 chlorobenzoyl) 2 methyl-5,6-dimethoxy-l-indole]acetate [I2 R is C H R is CH R is 4-ClC H CO; R is5,6-(CH O) Y is CH was prepared by reaction of 19.5 g. (0.059 mole) of3-(4- chlorobenzoyl) 2 methyl 5,6 dimethoxyindole with 10.4 g. (0.062mole) of ethyl bromoacetate in ml. of dry dimethylformamide in thepresence of 2.58 g. (0.065 mole) of a 61% suspension of sodium hydridein mineral oil using the procedure described above in Example 1(B) Therewas thus obtained ethyl a-[3-(4-chlorobenzoyl)-2-methyl-5,6-dimethoxy-l-indole]acetate as an elf-white solid.

(B) tit-[3 (4 chlorobenzoyl) 2-methyl-5,6-dimethoxy-1-ind0le]acetic acid[1: R is H; R is CH R is 4-ClC H CO; R is 5,6-(CH O) Y is CH wasprepared by saponification of the ethyl a-[3-(4-chlorobenzoyl)-2-methyl-5,6-dimethoxy 1 indole]acetate obtained above in Example 19(A) ina solution of 30 g. of potassium hydroxide in 200 ml. of methanol usingthe procedure described above in Example 1(C). The product wasrecrystallized from ethanol to give 16 g. of a-[3-(4-chlorobenzoyl) 2methyl 5,6 dimethoxy 1 indole]acetic acid as yellow needles, M.P.157-159 C.

Analysix-Calcd. for C H ClNO (percent): C, 61.93; H, 4.68; N, 3.61; Cl,9.14. Found (percent): C, 61.62; H, 4.53; N, 3.39; Cl, 9.02.

'EXAMPLE 20 (A) 3-(2,6 dimethoxybenzoyl) Z-methylindole [II: R2 is R3 isR4 is Was prepared by reaction of 76 g. (0.38 mole) of2,6-dimethoxybenzoyl chloride with the Grignard reagent prepared from 50g. (0.138 mole) of Z-methylindole and 138 ml. (0.38 mole) of a 3 M ethersolution of ethyl magnesium bromide in a total volume of about 500 ml.of diethyl ether and 100 ml. of tetrahydrofuran using the proceduredescribed above in Example 1(A). The crude product was recrystallizedonce from ethyl acetate and once from ethanol to give 46.5 g. of3-(2,6-dimethoxybenzoyl)-2- methylindole, M.P. 199200 C.

Analysis.-Calcd. for C H NO (percent): C, 73.20; H, 5.80; N, 4.74. Found(percent): C, 73.14; H, 5.84; N, 4.45.

(B) Ethyl a-[3 (2,6 dimethoxybenzoyl) Z-methyll-indole] acetate [1: R isC H R is CH R is 2,6-(CH O) C H CO; R is H; Y is CH was prepared byreaction of 20 g. (0.068 mole) of3-(2,6-dimethoxybenzoyl)-Z-methylindole with 11.3 g. (0.068 mole) ofethyl bromoacetate in ml. of dry dimethylformamide in the presence of 3g. (0.068 mole) of a 54% suspension of sodium hydride in mineral oilusing the procedure described above in Example 1(B). There was thusobtained ethyl lit-[3 (2,6 dimethoxybenzoyl) 2 methyl-l-indole] acetate.

(C) oz-[3 (2,6 dimethoxybenzoyl) 2 methyl-1- indole]acetic acidethanolate [Iz R is H; R is CH [R is 2,6 (CH O) C H CO; R is H; Y is CHwas prepared by saponification of the ethylu-[3-(2,6-dimethoxybenzoyl)-2-methyl-1-indole] acetate obtained above inExample 20(B) in a solution containing 60 g. of potassium hydroxide in450 ml. of methanol using the procedure described above in Example 1(C).The crude product was recrystallized from ethanol to give 18 g. ofoc-[3(2,6-dimethoxybenzoyl)-2-methy1-1-indole] acetic acid ethanolate asa White crystalline solid, M.P. 250 C. (dec.).

17 Analysis.-Calcd. for C H NO .C H O (percent): C, 66.15; H, 6.31; N,3.51. Found (percent): C, 66.39; H, 6.22; N, 3.28.

EXAMPLE 21 (A) Ethyl fl-[3-(2,6-dimethoxybenzoyl)-2-methyl-1indole]propionate [1: R is C 11 R is CH R is 2,6- (CH O) C H CO; R is H;Y is CH CH was prepared by reaction of 18 g. (0.06 mole) of3-(2,6-dimethoxy benzoyl)-2-methylindole with 12.1 g.- (0.067 mole) ofethyl B-bromopropionate in 150 ml. of dimethylformamide in the presenceof 2.3 g. (0.061 mole) of a 62% suspension of sodium hydride in mineraloil using the procedure described above in Example 1(B). There was thusobtained 20 g. of ethylB-[3-(2,6-dimethoxybenzoyl)-2-methy1-1-ind0le]propionate as an off-whitesolid.

(B) B [3 (2,6 dimethoxybenzoyl) 2 methyl-1- indole]propionic acid [1: Ris H; R is CH R is 2,6- (CH O) C H CO;-R is H; Y is CH CH was preparedby saponification of 20 g. (0.051 mole) of ethyl p-[3-(2,6-dimethoxybenzoyl)-2-methyl-1-indole]propionate in a-solution containing75 g. of potassium hydroxide in 500 ml. of methanol using the proceduredescribed above in Example 1(C). The crude product was recrystallizedfrom ethanol to give 9 g.- of /3[3-(2,6-dimethoxybenzoyl)-2-methyl-1-indole]propionic acid as an off-white solid, M.P. 195-1975"C.

Analysis.Calcd. for C H NO (percent): C, 68.65; H, 5.76; N, 3.81. Found(percent): C, 68.54; H, 5.85; N, 3.63.

EXAMPLE 22 (A) 3-(4-nitroben'zoyl)-2-methylindole [11: R is CH R is 4-NOC H CO; R is H] was prepared by reacting 71 g. (0.38 mole) of4-nitrobenzoy1 chloride with the Grignard reagent prepared from 50 g.(0.38 mole) of 2- methylindole and 138 ml. (0.41 mole) of a 3 M ethersolution of ethyl magnesium bromide in a total'of 400 ml. of absoluteether using the procedure described above in Example 1(A). The crudeproduct was recrystallized from ethanol to give 96 g. of3-(4-nitrobenzoyl)-2-methylindole, M.P. 230 C.

Analysis.-Calcd. for C H N O (percent): C, 68.56;

H, 4.32; N, 10.00. Found (percent): C, 68.82; H, 4.46;

y (B) L-[3-(4-I1lt10b6llZOYl) 2 methyl-1-indole]acetic acid [I: R is H;R is CH R is 4-NO C H CO; R is H; Y is CH was prepared by reacting 7.5g. (0.027

mole) of 3-(4-nitrobenzoyl)-2-methylindole'with 4.5 g.' (0.025 mole) ofethyl bromoacetate in 70 m1. of dimeth (A)3-benzoyl-2-methyl-S-methoxyindole [II: R is CH R is C H CO; R is 5-CHO] Was prepared by reaction of'61 g. (0.43 mole) of benzoyl chloridewith the Grignard reagent prepared from 35 g. (0.22 mole) of2-methyl-5-methoxyindole and 80 ml. (0.24 mole), of a 3 M ether solutionof ethyl magnesium bromide in a total volume of about 430 ml. oftetrahydrofuran using the procedure described above in Example 1(A). Thecrude product was recrystallized from ethanol to give 26.5 g. of3-benzoyl-2-methyl-5-methoxyindole, M.P. 196198 C.

' Analysis.--Ca1cd. for C17H15NO2 (percent): C, 76.96; H, 5.70; N, 5.28.Found (percent): C, 77.21; H, 5.66; N, 5.01.

(B) Ethyl u-(3-benzoyl-2-methyl-5-methoxy-l-indole) acetate [1: R is C HR is CH R is C H CO; R is 5-CH O; Y is CH was prepared by reaction of6.6 g. (0.04 mole) of ethyl bro'moacetate with g. (0.04 mole) of3-benzoy1-2-methyl-S-methoxyindole in 100 ml. of anhydrousdimethylformamide in the presence of 1.65 g. (0.042 mole) of a 61%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained ethyla-(B-benzoyl-2-methyl-5-methoxy-l-indole)acetate as a yellow gum.

(C) a (3-benzoyl-2-methyl-S-methoxy-l-indole)acetic acid [1: R is H; Ris CH R is C H CO; R is 5-CH O; Y is CH was prepared by saponificationof the ethyl a-(3-benzoy1-2-methyl-S-methoxy 1 indole)acetate obtainedabove in Example 23(B) in a solution of ethanol and aqueous sodiumhydroxide using the procedure described above in Example 1(C). The crudeproduct was recrystallized from ethyl acetate to give 63 g. of a-(3-benzoyl-2-methyl-5-methoxy-l-indole)acetic acid, M.P. 202.5205 C.

Analysis.-Calcd. for C19H17NO4 (percent): C, 70.57; H, 5.30; N, 4.33.Found (percent): C, 70.87; H, 5.33; N, 4.03.

EXAMPLE 24 (A) Ethyl B-(3-benzoyl-2-methyl-S-methoxy-l-indole)propionate [1: R is C H R is CH R is C H CO; R is 5-CH O; Y is CH CH wasprepared by reaction of 7.16 g. (0.04 mole) of ethyl fl-bromopropionatewith 10 g. (0.04 mole) of 3-benzoyl-2-methyl-5-methoxyindole in 100 ml.of dry dimethylformamide in the presence of 1.65 g. (0.042 mole) of a61% suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B). There was thus obtained ethyl B-(3benzoyl-2-methyl-5-methoxy 1 indole)-propionate as a light brown gum.

Y (B) ,8 (3-benzoyl-2-methyl-5-methoxy-l-indole)propionic acid [1: R isH; R is CH R is C H CO; R is 5-CH O; Y is CH CH was prepared bysaponification of,

'- the ethyl p-(3-benzoyl-2-methyl-5-methoxy-1-indole)propionateobtained above in Example 24(A) in a solution containing g. of potassiumhydroxide in 100 ml. of.

methanol using the procedure described above in Example 1(C). The crudeproduct'was recrystallized from ethanol to give 8.6 g. offl-(3-benzoyl-2-methyl-5- methoxy-1-indole)propionic acid, M.P. 215-2185C.

Analysis.-Calcd. for C H NO (percent): C, 71.20; H, 5:68; N, 4.15. Found(percent): C, 71.47; H, 5.76; N, 3.73.

EXAMPLE 25 (A) 3-(4-chlorobenzoyl)-2-methyl-5 methoxyindole R2 is R3 isR4 is was prepared by reaction of 32.4 g. (0.18 mole) of 4-ehlorobenzoylchloride with the Grignard reagent prepared from 15 g. (0.093 mole) of2-methyl-5-methoxyind0le and ml. (0.11 mole) of a 3 M ether solution ofethyl magnesium bromide in a total volume of 200 ml. of dry ether and150 ml. of tetrahydrofuran using the procedure described above inExample 1(A). The crude product was dissolved in 200 ml. of 15%methanolic potassium hydroxide, and diluted to the cloud point withwater. The crude product, which separated on cooling, was collected,washed with methanol/Water and recrystallized from methanol to give 12g. of 3-(4-chlorobenzoyl)-2-methyl-5- 1 methoxyindole, M.P. 189l90.5 C.

(B) fl-[3-(4-chlorobenzoyl)-2-methyl-5-methoxy l-indole]propionic acid[1: R is H; R is CH R is 4 ClC H CO; R is 5-CH O; Y is CHZCHg] wasprepared by reaction of 4.95 g. (0.035 mole) of ethyl fl-bromopropionatewith 10.5 g. (0.035 mole) of3-(4-chlorobenzoyl)-2-methyl-5-methoxyindole in ml. of anhydrousdimethylformamide in the presence of 1.5 g. (0.038 mole) of a 60%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B),

and saponification of the resulting ethyl,B-[3-(4-chlorobenzoyl)-2-methyl-5-methoxy-1 indole]propionate in asolution of 20 g. of potassium hydroxide in 200 ml. of methanol usingthe procedure described above in Example 1(C). The crude product wasrecrystallized two times from acetonitrile to give 8.9 g. offi-[3-(4-chlorobenzoyl)- 2-methyl-5-methoxy-l-indole]propionic acid,M.P. 204- 205 C.

Analysis.Calcd. for C H ClNO (percent): C, 64.60; H, 4.88; N, 3.77.Found (percent): C, 64.78; H, 4.81; N, 3.60.

EXAMPLE 26 a-(3-benzoyl-2-methyl-l-indole)propionic acid [I: R, is H; Ris CH R is C H CO; R is H; Y is CH CH] was prepared by reaction of 23.5g. (0.1 mole) of 3-benzoyl- 2-methylindole with 18.1 g. (0.1 mole) ofethyl a-bromopropionate in 200 ml. of dry dimethylformamide in thepresence of 3.94 g. (0.1 mole) of a 61% suspension of sodium hydride inmineral oil using the procedure described above in Example 1(B), andsaponification of the resulting ethyla-(3-benzoyl-2-methyl-1-indole)propiomate in a solution of 50 g. ofpotassium hydroxide in 500 ml. of methanol using the procedure describedabove in Example 1( C). The crude product was recrystallized fromabsolute ethanol to give 8.5 g. of a-(3-benzoyl-2-methyl-1-indole)propionic acid, M.P. 225-227 C.

Analysis.Calcd. for C H NO (percent): C, 74.25; H, 5.58; N, 4.56. Found(percent): C, 74.16; H, 5.58; N, 4.30.

EXAMPLE 27 a-[3-(4-chlorobenzoyl)-2-methyl l indole]propionic acid [I: Ris H; R is CH R is 4-ClC H CO; R is H; Y is CHgCH] was prepared byreaction of g. (0.074 mole) of 3-(4-chlorobenzoyl)-2-methylindole with13.3 g. (0.074 mole) of ethyl a-bromopropionate in 200ml. ofdimethylformamide in the presence of 3.0 g. (0.075 mole) of a 61%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B), and saponification of the resultingethyl a- [3-(4-chlorobenzoyl)-2-methyl-l-ind0le1propionate in a solutionof 50 g. of potassium hydroxide in 400 ml. of methanol using theprocedure described above in Example 1(C). The crude product wasrecrystallized from ethanol/water to give a-[3-(4-chlorobenzoyl)-2-methyl-1 indole]propionic acid, M.P. 116 C.

Analysis.Calcd. for C H ClNO (percent): C, 66.76; H, 4.72; N, 4.10; Cl,10.37. Found (percent): C, 66.93; H, 5.08; N, 3.78; Cl, 10.51.

EXAMPLE 28 5 [3-(4-rnethoxybenzoyl)-2-methyl-l-indo1e]propionic acid [1:R is H; R is CH R is 4-CH OC H CO; R is H; Y is CH CH was prepared byreaction of 16 g. (0.06 mole) of 3-(4-methoxybenzoyl)-2-methylindolewith 11.5 g. (0.06 mole) of ethyl ,B-bromopropionate in 150 ml. ofdimethylformamide in the presence of 2.5 g. (0.063 mole) of a 60%suspension of sodium hydride in mineral oil using the proceduredescribed above in Example 1(B), and saponification of the resultingethyl fi-[3-(4-methoxybenzoyl)-2-methyl-1-indole]propionate withmethanolic potassium hydroxide using the procedure described above inExample 1(C). The crude product was recrystallized once from ethylacetate and once from acetonitrile to give 10.3 g. of[3-[3-(4-methoxybenzoyl)-2-methyl-1-indole]propionic acid, M.P. 177178.5C.

Analysis.-Calcd. for C H NO (percent): C, 17.20; H, 5.68; N, 4.15. Found(percent): C, 71.39; H, 5.66; N, 4.08. K

EXAMPLE 29 (A) Ethyl B-[3-(4-chlorobenzoyl)-2-methyl-5,6dimethoxy-l-indole]propionate [I: R, is C H R is CH R3 is R4 iS 5,6-(CHO) Y is was prepared by reaction of 5.5 g. (0.03 mole) of ethyl {3- 20bromopropionate with 9.5 g. (0.03 mole) of 3-(4chlorobenzoyl)-2-methyl-5,6-dimethoxyindole in ml. of dimethylformamidein the presence of 1.25 g. (0.03 mole) of a 61% suspension of sodiumhydride in mineral oil using the procedure described above in Example1(B). There was thus obtained ethyl ,8-[3-(4-chlorobenzoyl)-2-methyl-5,6-dimethoxy-l-indole1propionate as a cream colored gum.

(B) ,8 [3-(4-chlorobenzoyl)-2-methyl-5,6-dimethoxy- 1-indole1propionicacid [1: R is H; R is CH R is 4- ClC H CO; R is 5,6-(CH O) Y is CH CHwas prepared by saponification of the ethyl[3-[3-(4-chlorobenzoyl)-2-methyl-5,6dimethoxy 1 indole]propionateobtained above in Example 29(A in a solution of potassium hydroxide inethanol using the procedure described above in Example 1(C). The crudeproduct was recrystala lized from ethyl acetate to give 5.1 g. offi-[3-(4-chlorobenzoyl )-2-methyl-5,6-dimethoxy1 indole]propionic acid,M.P. 193.5-195.5 C.

Analysis.Calcd. for C H ClNO (percent): C, 62.76; H, 5.01; N, 3.48; Cl,8.82. Found (percent): C, 62.57; H, 5.22; N, 3.22; CI, 8.55.

EXAMPLE 30 (A) 3-(4-chlorobenzoyl)-2-methyl-5-fiuoroindole [11: R is CHR is 4-CIC H CO; R is 5-F] was prepared by reaction of 25 g. (0.14 mole)of 4-ch1orobenzoyl chloride with the Grignard reagent prepared from 12g. (0.08 mole) of Z-methyl-S-fluoroindole and 30 ml. (0.09 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 100 ml.of tetrahydrofuran using the procedure described above in Example 1(A).There was thus obtained 8 g. of 3-(4-chlorobenzoyl)-2-methyl-5-fiuoroindole, M.P. 231-233 C.

(B) oz- [3 (4-chlorobenzoyl -2-methyl-5-fluoro-l-indole] acetic acid [1:R is H; R is CH R is 4-ClC H CO; R is 5-F; Y is CH was prepared byreaction of 2.4 g. (0.014 mole) of ethyl bromoacetate with 4 g. (0.015mole) of 3-(4-chlorobenzoyl)-2-methyl-5-fluoroindole in 40 ml. ofdimethylformamide in the presence of 0.6 g. (0.015 mole) of a 60%suspension of sodium hydride in mineral oil, and saponification of theresulting ethyl DC-[3- (4-chlorobenzoyl)-2-methyl-5-fluoroindole]acetatein a solution containing 10 g. of potassium hydroxide in 100 ml. ofmethanol all according to the procedure described above in Example 1(B)and (C). There was thus obtained 4.8 g. ofa-[3-(4-chlorobenzoyl)-2-methyl-5-fiuoro-1indole]acetic acid.

EXAMPLE 31 ,8 [3 (4 chlorobenzoyl)-2-methyl-5-fluoro-l-indole] propionicacid [I: R is H; R is CH R is 4-ClC H CO; R is S-F; Y is CH CH wasprepared by reaction of 2.5 g. (0.014 mole) of ethyl fl-bromopropionatewith 3.8-

(A) 3-benzoyl-2-methyl-5-fiuoroindole [11: R is CH R is C H CO; R is5-F] was prepared by reaction of 22.5 g. (0.16 mole) of benzoyl chloridewith the Grignard reagent prepared from 12 g. (0.08 mole) of 2-methyl-5-fluoroindole and 30 ml. (0.09 mole) of a 3 M ether solution of ethylmagnesium bromide in a total volume of about 100 ml. of tetrahydrofuranusing the procedure described above in Example 1 (A). The crude product21 was recrystallized from methanol to give 8.6 g. of3-benzoyl-Z-methyl-S-fluoroindole, M.P. 232234 C.

(B) 12- 3-benzoyl-2-methyl-5 -fiuoro-1-indole acetic acid [1: R H; R isCH R is C H CO; R is S-F; Y is CH was prepared by reacting 2.9 g. (0.017mole) of ethyl bromoacetate with 4 g. (0.017 mole) of 3-benzoyl-2-methyl-S-fiuoroindole in 40 ml. of dimethylformamide in the presence of0.68 g. (0.017 mole) of a 60% suspension of sodium hydride in mineraloil, and saponification of the resulting ethyl-(3-benzoyl-2-methyl-5-fiuoro-l-indole)acetate in a solution containing-10 g. of potassium hydroxide in 100 ml. of methanol all according to theprocedure described above in Example 1(B) and (C). The crude product wasrecrystallized two times from acetonitrile to give 2.2 g. ofa-(3-benzoyl-2-methyl-S-fluoro-1 indole)acetic acid, M.P. 253-255 C. V

' EXAMPLE 33 13 (3-benzoyl-2-methyl-5 fiuoro-l-indole)propionic acid [1:R is H; R is CH R is'C H CO; R is 5-F; Y is CH CH was prepared byreaction of 3.05 g. (0.017 mole) of ethyl B-bromopropionate with 4.0 g.(0.17 mole) of 3-benzoyl-2-methyl-5-fiuoroindole in 35 ml. of dimethylformamide in the presence of 0.68 g. (0.018 mole) of a 60% suspension ofsodium hydride in mineral oil, and

saponification of the resulting ethyl B-(3-benzoyl-2-methyl-S-fluoro-l-indole)propionate in a solution containing 12 g. of potassiumhydroxide in 100 ml. of methanol all according to the proceduredescribed above in Example 1(B) and (C). The crude product wasrecrystallized two times from acetonitrile to give 3.4 g. ofB-(3-benzoyl-2-methyl- S-fluoro-1-indole)propionic acid, M.P. 2 28230 C.

EXAMPLE 34 (A) 3-(2,6-dichlorobenzoyl) 2 methylindole [11: R is CH R is2,6-Cl C H CO; R is H] was prepared by reaction of 105 g. (0.5 mole) of2,6-dichlorobenzoyl chloride with the Grignard reagent prepared from65.6 g. (0.5 mole) of Z-methylindole and 180 ml. (0.54 mole) of a 3 Mether solution of ethyl magnesium bromide in a total volume of about 600ml. of absolute diethyl ether and 100 ml. of tetrahydrofuran using theprocedure described above in Example 1(A). The crude product wasrecrystallized from ethanol to give 50 g. of3-(2,6-dichlorobenzoyl)-2-methylindole, M.P. 131133 C.

(B) u-[3-(2,6-dichlorobenzoyl-2-methyl-l-indole]acetic acid [R1 iS R2 iSR3 iS 2,6-Cl C H CO; R4 is Y is CH was prepared by reaction of 9.8 g.(0.057 mole) of ethyl bromoacetate with 17 g. (0.056 mole) of 3 (2 ,6-dichlorobenzoyl)-2-methylindole in 150 ml. of dimethylformamide' in thepresence of 2.2 g. (0.054 mole) of a 60% suspension of sodium hydride inmineral oil, and saponification of the resulting ethylrx-[3-(2,6-dichlorobenzoyl)-2-methyl-1- indole]acetate in a solution ofg. of potassium hydroxide in 400 ml. of hot methanol all according tothe procedure described above in Example 1(B) and (C). The crude productwas recrystallized from an ethyl acetate/cyclohexane mixture giving 8.9of oz- 3- 2,6-dichlorobenzoyl -2-methyll -indole] acetic acid, M.P.242243 C.

EXAMPLE [3-[3-(2,6-dichlorobenzoyl) 2 methyl 1- indole] propionic acid[I: R is H; R is CH R is 2,6- Cl C H CO; R is H; Y is CH CH was preparedby reaction of 10.1 g. (0.056 mole) of ethyl fi-bromopropiomate with17g. (0.56 mole) of 3-(2,6-dichlorobenz'oyl)-2 methylindole in 150 ml.of anhydrous dimethylformamide in the presence of 2.2 g. (0.055 mole) ofa 60% suspension of sodium hydride in mineral oil, and saponification ofthe resulting ethyl B-[3-(2,6-dichlorobenzoyl)-2-methyl-l-indole]propionate in a solution containing 30 g. of potassiumhydroxide in 350 ml. of methanol all according to the proceduredescribed above in Example 1(B) and C. The crude product wasrecrystallized from an ethyl acetate/cyclohexane mixture to give 12 g.of 8-[3-(2,6-

22 dichlorobenzoyl)-2-methyl-1-indole]propionic acid, M.P. 194196 C.

EXAMPLE 36 ,8,- 3-benzoyl-2-methyl-l -indole) -a-methylpropionic acid[1: R is H; R is CH R is C H CO; R is H; Y is CH CH(CH Was prepared byreaction of 8.4 g. (0.043 mole) of ethyl a-bromoisobutyrate with 10 g.(0.043 mole) of 3-benzoyl-2-methylindole in ml. of anhydrousdimethylformamide in the presence of 1.7 g. (0.043 mole) of a 60%suspension of sodium hydride in mineral oil, and saponification of theresulting ethyl fi-(3-benzoyl- Z-methyl-I-indole)-a-methyl-propionate ina solution containing 30 g. of potassium hydroxide in 300 ml. ofmethanol all according to the procedure described above in Example 1(B)and (C). The product was recrystallized once from isopropanol and oncefrom ethyl acetate to give 3.5 g. of ,8(3-benzoyl-2-methyl-1-indole)-a-methylpropionic acid, M.P. 194-196 C.

A nalysis.Calcd. for C H NO (percent): C, 74.74; H, 5.96; N, 4.36. Found(percent): C, 75.03; H, 5.94; N, 4.05.

1 EXAMPLE 37 (A) 3-(2-thenoyl)-2-methylindole [11: R is CH R is 2-C HS-CO; R is H] was prepared by reaction of 57 g. (0.38 mole) ofthiophene-Z-carboxylic acid chloride with the Grignard reagent preparedfrom 50 g. (0.038 mole) of Z-methylindole and 138 ml. (0.41 mole) of a 3M ether solution of ethyl magnesium bromide in a total of 600 ml. ofabsolute diethyl ether using the procedure described above in Example1(A). The crude product was recrystallized from ethanol to give 37 g. of3- 2-thenoyl -2-methylindole.

(B) a-[3-(2-thenoyl)-2-methyl-1-indole]acetic acid [1: R1 is R2 is R3 is2-C4H3S-CO; R4 is Y is CH was prepared by reaction of 6.7 g. (0.04 mole)of ethyl bromoacetate with 10 g. (0.04 mole) of3-(2-thenoyl)-2-methylindole in 100 ml. of anhydrous dimethylformamidein the presence of 1.65 g. of (0.04 mole) of a 60% suspension of sodiumhydride in mineral oil, and

Y saponification of the resulting ethyl a-[3-(2-thenoyl)-2-methyl-1-indole1-acetate in a solution of potassium hydroxide inmethanol all according to the procedure de' scribed above in Example1(B) and (C).

EXAMPLE 3 8 EXAMPLE 39 [3-[3-(2-thenoyl)-2-methyl-1-indole]propionicacid [1: R is H; R is CH R is 2-C H S-CO; R is H; Y is CH CH wasprepared by reaction of 7 .5 g. (0.42 mole) of ethyl B-bromopropionatewith 10 g. (0.042 mole) of 3- (Z-thenoyl)-2-methylindole in 100 ml. ofdry dimethylformamide in the presence of 1.75 g. (0.045 mole) of a 61%suspension of sodium hydride in mineral oil, and saponification of theresulting ethyl fl-[3-(2-thenoyl)-2- methyl-l-indole]propionate in asolution containing potassium hydroxide in methanol all according to theprocedure described above in Example 1(B) and (C).

EXAMPLE 40 Ethyl a [3-(4-nitrobenzoyl)-2-methyl-l-indole] acetate [1: R1is C2H5; R2 is R3 iS R4 is Y is CH was prepared by reaction of 28.5 g.(0.17 mole) of ethyl bromoacetate with 45.5 g. (0.16 mole) of 3-(4-nitrobenzoyl)-2-methylindole in 300 ml. of dry dimethylformamide in thepresence of 7.05 g. (0.18 mole) of a 61% suspension of sodium hydride inmineral oil using the procedure described above in Example 1(B). Thecrude product was recrystallized from methanol to give 36 g. of ethyla-[3-(4-nitrobenzoyl)-2-methyl-1-indol]- acetate, M.P. 155-158 C.

EXAMPLE 41 (A) Ethyl a [3-(4-aminobenzoyl)-2-methyl-1-indole'] acetateR1 is C2H5; R2 is R3 is 4NH C H CO; R is H; Y is CH ].-Ten grams (0.027mole) of ethyl u- [3-(4-nitrobenzoyl)-2-rnethyl-1 indole]acetate weredissolved in 200 ml. of ethyl acetate and 50 ml. of methanol and reducedwith hydrogen at room temperature in a Parr shaker over 1 g. of a 10%palladium-on-charcoal catalyst using an initial hydrogen pressure ofabout 50 pounds p.s.i. When reduction was complete, the catalyst wasremoved by filtration, the filtrate taken to dryness, and the residuerecrystallized from a chloroform/hexane mixture giving 10 g. of ethyla-[3-(4-aminobenzoyl)-2- methyl-l-indoleJacetate, M.P. 8588.5 C.

(B) at [3-(4-aminobenzoyl)-2-methyl-1-indole]acetic acid [I: R is H; Ris CH R is 4-NH C H CO; R is H; Y is CH is prepared by saponification ofthe ethyl n: [3 (4-aminobenzoyl)-2-methyl-l-indoleJacetate obtainedabove in Example 41(A) in ethanolic sodium hydroxide using the proceduredescribed above in Example 1(C).

EXAMPLE 42 (A) 3-benzoyl-2-t-butylindole [11: R is (CH C; R is C H CO; Ris H].-A mixture of 54 g. (0.5 mole) of phenylhydrazine and 50 g. (0.5mole) of pinacolone in 300 ml. of benzene was refluxed for seven hoursunder a Dean-Stark trap, during which time 6 ml. of water was collected.The resulting solution was taken to dryness in vacuo, and the resultinglight brown liquid was heated slowly to 100 C, with 400 g. (2.93 moles)of anhydrous zinc chloride. The heating bath was then removed, and thetemperature of the reaction mixture rose rapidly to 150 C. The mixturewas cooled in a water bath to 130 C. and then heated for twenty minutesat 190 C. After cooling, the mixture was mixed with water and ethylacetate, the organic phase was separated, washed once with dilute acid,once with dilute sodium bicarbonate, and once with saturated brine.After drying the organic solution over anhydrous sodium sulfate, thesolution was taken in dryness, and the residual brown oil was distilledin vacuo, the product being collected at 8 5-95 C./ 0.05 mm. There wasthus obtained 46 g. of Z-t-butylindole as a colorless solid, M.P. 6569C.

Reaction of 31 g. (0.22 mole) of benzoyl chloride with the Grignardreagent prepared from 19 g. (0.11 mole) of the 2-t-butylindole preparedabove and 40 ml. (0.12 mole) of a 3 M ether solution of ethyl magnesiumbromide in a total of 210 ml. of tetrahydrofuran using the proceduredescribed above in Example 1(A), and recrystallization of the crudeproduct from ethanol gave 3-benzoyl-2-tbutylindole, M.P. 215-220" C.

(B) or. (3-benzoyl-2-t-butyl-l-indole)acetic acid [1: R is H; R is (CHC; R is C H CO; R is H; Y is CH is prepared by reaction of the3-benzoyl-2-t-butylindole obtained above in Example 42(A) with ethylbromoacetate in dimethylformamide in the presence of sodium hydride, andsaponification of the resulting ethyl a-(3-benzoyl-2-t-butyl-l-indole)acetate all according to the proceduredescribed above in Example 1(B) and (C).

EXAMPLE 43 6-(3-benzoyl-2-t-butyl-1-indole)propionic acid [I: R is R2 isR3 is R4 is Y is is perpared by reaction of 3-benzoyl-2-t-butylindolewith ethyl B-bromopropionate in dimethylformamide in the presence ofsodium hydride, and saponification of the resulting ethyl B (3 benzoyl-2t-butyl-1-indole)propionate all according to the procedure described inExample 1(B) and (C). I t

- EXAMPLE 44 I (A) '3-(4-chlorobenzoyl)-2-t-butylindole [Hz R is (CH C;R is 4'-ClC H CO; R is H] is preared by re action, in anhydrous ether ortetrahydrofuran, of 4-chlorobenzoyl chloride with the Grignard reagentprepared from 2-t-butylindole and methylm'agnesium bromide using theprocedure described above in Example 1(A).

(B) a [3-(4-chlorobenzoyl)-2-t-butyl-1-ii1dole]acetic [II R1 is R2 is[R3 R4 is H; Y isCH is prepared by reaction of ethyl bro'mo acetate with3-(4-chlorobenzoyl)-2-t-butylindole in dry dimethylformamide in thepresence of sodium'hydride, and saponification of the resulting ethyla-[3-(4-chlorobenzoyl)r2-t-butyl l indole]acetate all according to theprocedure described above in Example 1(B) and (C).

. EXAMPLE45 I '5 [3 (4-chlorobenzoyl)-2-t-butyl-1-indole]propionic acid[1: R is H; R is (CH C; R3 is 4-ClC H CO; R is H; Y is CH 'CH isprepared by reaction of ethyl B- bromopropionate with -3 (4chlorobenzoyl)-2-t-butylin dole in dry dimethylformamide in the presenceof sodium hydride, and saponification of the resulting ethyl ,B-[3-(4-chlorobenzoyl)-2-t-butyl-1-indole]propionate all according to theprocedure described above in Example 1(B) and (C). I

EXAMPLE 46 p a [3 (4-chlorobenzoyl)-2-rnethyl-5-methoxy-l-indole] aceticacid [1: R is H; R is CH R is 4-ClC H CO; R is 5-CH O; Y is CH isprepared by reaction of ethyl bromoacetate with3-(4-ch1orobenzoyl)-2-methyl-5-meth oxyindole in dry dimethylformamidein the presence of sodium hydride, and saponification of the resultingethyl a [3 (4-chlorobenzoyl)-2-methyl-5-methoxy-l-indole] acetate allaccording to the procedure described abovein Example 1(B) and (C).

EXAMP-LE 47 [3- 3- (4-nitroben'zoyl) -2-methyl-1-indole] propionic. acid[I: R is H; R is CH R is 4-NO C H CO; R is H; Y is CH 'CH is prepared byreatcion of ethyl B-bromopropionate with3-(4-nitrobenzoyl)-2-methylindole in dry dimethylformamide in thepresence of sodium hydride, and saponification of the resulting ethyl13-[3-(4-nitrobenzoyl)- Z-methyl-1-indole]propionate all according tothe procedure described above in Example 1(B) and (C) EXAMPLE 481 8 [3(4-aminolbenzoyl)-2-rnethyl-1-indole]propionic acid [1: R is H; R is CHR is 4- NH C H4OO; R is H; Y is CH CH is prepared by reduction withhydrogen over a palladium-on-channel catalyst of the18-[3-(4-nitrobenzoyl) 2 methyl l-indole]propionic acid described abovein Example 47 using the procedure described abov in Example 41 (A).

EXAMPLE 49 medium. 7

EXAMPLE 50 ,e [3'- (4- dimethylaminobenzoyl)-2 -rnethyl-.1-ind olejpropionic acid [1: R is H; R is CH R is V v I R is H; Y is CH CH isprepared by heating 8-[3-(4- 25 aminobenzoyl)-2-methyl 1indole]propionic acid with formaldehyde in excess formic acid, andisolation of the product from a neutral medium.

[EXAMPLE 51 (A) 3-(4-t-butylbenzoyl)-2-methylindole ['11: R is CH R is4-(CH CC H CO; R is H] is prepared by reaction, in dry ether ortetrahydrofuran, of 4-t-butylbenzoyl chloride with the Grignard reagentprepared-from Z-methylindole and methyl magnesium bromide using the-EXAMPLE 52 V ,6 [3 (4-t-butylbenzoylbZ-methyl-1-indole]propionic acid[1: R is H; R is CH R is 4-(CI-I CC H CO; R is H; Y is CH CH J isprepared by reaction of ethyl bromopropionate with3-(4-t-butylbenzoyl)-2-methylindole in dry dimethylformamide inthe-presence of sodium 1 hydride, and saponification of the resultingethyl ,8-[3-(4:

t-butylbenzoyl)-2-methyl- 1-indole]-propionate all accord,-

ing to the procedure described above in Example 1(B) and (C). k

EXAMPLE 53 (A) 3-benzoyl2,S-dimethylindole [Hz R is CH R is C H CO; R is5-CH isprepared by reaction, in dry ether or tetrahydrofuran, of benzoylchloride with the Grignard reagent prepared'fro'm 2,5-dimethylindle andmethyl magnesium bromide above in Example 1(A I (B)a-(3-benzoyl-2,5-dimethyl-l-indole)acetic acid [I2 R is H; R is CH R isCH C0; R is 5-CH Y is CH is prepared by reaction ofethyl'bromoacetatewith 3- benzoyl-2,S-dimethylindole in drydimethylformamide in the presence of sodium hydride, and saponificationof the resulting ethyl a-(3:benzoyl 2,5-dime,thyl-l-indole) acetate all"according to the procedure described above in Ex-.

ample 1(B) and (Q).

EXAMPLE 54 5-(3benzoyl-2,S-dirnethylQl-indole)propionic acid [I R1 is R2is R3 is R3 is Y is CH CH is prepared by reaction of ethyl,e-bromopropionate with 3-benzoy1-2,5 dimethylindole'indrydimethylformamide in the presence of sodium hydride, and saponificationof the resulting ethyl 8-(3-benzoyl-2,5 dimethyl 1-indole)propionate allaccording to the procedure described'abovein Example 1(B) and (C).

' EXAMPLE 55 (A) 3-(2-furoyl) 2 -methyl-6;hydroxyindole [11: R is] CH R'is 2-C H O-CO; R is 6-HO] is prepared by reaction, in dry ether'ortetrahydrofuran, of 2, furancarb0ny1 chloride with the Grignard reagentprepared from 2-meth yl-6-hydroxyindole and methyl magnesium bromideusing the procedure described above in 'Example 1(A).

' (B) "y [3-(2-furoyl) 2methyl-6-hydroxy-l-indole]butyric acid [I: R1 isH; R is CH R is 2-C H O-CO; R is 6-HO; Y is (CH is prepared by reactionof ethyl y-bromobutyrat'e with 3-(2 furoy1)-2-methyl-6-hydroxyindole indry dimethylformamide in the presence of sodium hydride, andsaponification of 'the' resulting ethyl 'y- 3- Z-furoyl)Z-methyl-S-hydroXy-l -indole] butyrate all according to theprocedure'described abovein'Ex'ample 1(B) and(C).

(A) 3-(2-pyridinecarbonyl)-2-ethylindole 11; R is C H R3 is Z-CSHQN-CO;R is IE] is prepared by re action, in dry ether or tetrahydrofuran, ofZ-pyridinecarbonyl chloride with the Grignard reagent prepared from2-ethylindole and methyl magnesium bromide using the procedure describedabove in Example 1(A).

prepared by reaction, in dry ether or tetrahydrofuran, of3-pyrid1necarbonyl chloride with Grignard reagent pre-' pared from2-methyl-6-trifluoromethylindole and methyl using the proceduredescribed magnesium iodide using the procedure described above inExample 1(A).

(B) a [3-(3-pyridinecarbonyl)-2-methyl-6-trifluoromethyl-1-indole1aceticacid [I: R is H; R is CH R is 3-,C H N-CO; R is 6-CF Y is CH is preparedby re action of ethyl bromoacetate with 3-(3-pyridinecarbonyl)-Z-methyl-6-trifluoromethylindole in dry dimethylfo'rmamide in thepresence of sodium hydride, and saponification of the resulting ethyla-[3-(3-pyridinecarb0nyl)-2- methyl-fi-trifiuoromethyl-l-indole] acetateall according to the procedure described above in Example 1(B) and (C).

EXAMPLE 58 (A) 3-(4-pyridinecarbonyl)-2-methyl-5,6-methylenedioxyindole[11: R is CH R is 4-C H N-C'O; R is 5,6-OCH O] is prepared by reaction,in dry ether or tetrahydrofuran, of 4-pyridinecarbonyl chloride with theGrignard reagent prepared from 2-methyl-5,6-methylenedioxyindole andmethyl magnesium bromide using the procedure described above in Example1(A).

' (B)w[3-(4-pyridinecarbonyl)-2-methyl-5,6-methylenedioxy-1-ind0le1aceticacid [1: R is H; R is CH R is 4-C H N-CO; R is 5,6-OCH O; Y is CH isprepared by reaction of ethyl bromoacetatewith3-(4-pyridinecarbonyl)-2-methyl-5,fi-methylenedioxyindole in drydimethylformamide in the presence of sodium hydride, and saponificationof the resulting ethyl a[3-(4-pyridinecarbonyl)-2-methyl-5,6-methylenedioxyl-indole] acetate all according to theprocedure described above in Example 1"(B) and c EXAMPLE 59 (A) 3(4-isoxazolecarbonyl)-2-methyl-5,6-ethylenedioxyindole [11: R is CH R is4-C H N-CO; R is 5,6-OCH CH O]-is prepared by reaction, in dry ether ortetrahydrofuran, of 4isoxazolecarbonyl chloride with the Grignardreagent prepared from 2-methyl-5,6-ethylenedioxyindoleand methylmagnesium bromide using the pro cedure described above in Example 1(A).

' (B)u-[3+(4-isoxazolecarb0nyl)-2-methyl-5,6-ethylenedioxy-l-indole]acetate[Iz R is H; R is CH R is 4C H NO-CO; R is 5,6-OCH CH O; Y is CH is preparedby reaction of ethyl bromoacetate with3-(4-isoxazolecarbonyl)-2-methyl-5,6-ethylenedioxyindole in drydimethylformamide' in the presence of sodium hydride, and saponificationof the resulting ethyla-[3-(4t-isoxazolecarbonyl)-2-methyl-5,6-ethylenedioxy-1- indoleJacetateall according to the procedure. described above in Example 1(B) and (C).

. EXAMPLE '60 methylindole and methyl magnesium bromide using theprocedure described above in Example 1(A).

- (B) a- [3 (4-thiazolecarb'ony1)-2-methyl-1-indole] acetic R1 R2 is R3iS 4-C3HQNS-COQR4 lS Y is CH is prepared by reaction of ethylbromoacetate with 3-(4-thiazolecarbonyl)-2-methylind0le in drydimethylformanide in the presence of sodium hydride, and saponificationof the resulting ethyla-[3-(4-thiazolecarbonyl)-2-methyl-1-indole]acetate a1 1 according tothe procedure described above in Example 1(B) and (C 27 EXAMPLE 61 (A)3-(5-thiazolecarbonyl)-2-methylindole [11: R is CH R is -C H NS-CO; R isH] is prepared by reaction, in dry ether or tetrahydrofuran, ofS-thiazolecarbonyl chloride with the Grignard reagent prepared from2-methylindole and methyl magnesium bromide using the proceduredescribed above in Example 1(A).

(B) a-[3-(S-thiazolecarbonyl)-2-methyl 1 indole] acetic acid [I: R is H;R is CH R is 5-C H NS-CO; R is H; Y is CH is prepared by recation ofethyl bromoacetate with 3-(S-thiazolecarbonyl)-2-methylindole in drydimethylformamide in the presence of sodium hydride, and saponificationof the resulting ethyl oc-[3-(5-thiazolecarbonyl)-2-methyl-1-i-ndole]acetate all according to theprocedure described above in Example 1(B) and (C).

EXAMPLE 62 (A) 3-(4-isothiazolecarbonyl)-2-methylindole [III R is CH Ris 4-C H NS-CO; R is H] is prepared by reaction, in dry ether ortetrahydrofuran, of 4-isothiazolecarbonyl chloride with the Grignardreagent prepared from 2-methylindole and methyl magnesium bromide usingthe procedure described above in Example 1(A).

(B) a-[3-(4-isothiazolecarbonyl)-2-methyl-1 indole] acetic acid [I: R isH; R is CH R is 4-C H NS-CO; R is H; Y is CH is prepared by reaction ofethyl bromoacetate with 3-(4-isothiazolecarbonyl)-2 methylindole in drydimethylformamide in the presence of sodium hydride, and saponificationof the resulting ethyl a-[3-(4-isothiazolecarbonyl)-2-methyl-1indo1e1acetate all according to the procedure described above in Example1(B) and (C).

EXAMPLE 63 3-(5-isothiazolecarbonyl)-2-methylindole [II: R is CH R is5-C H NS-CO; R is H] is prepared by reaction, in dry ether ortetrahydrofuran, of 5-isothiazolecarbonyl chloride with the Grignardreagent prepared from Z-methylindole and methyl magnesium bromide usingthe procedure described above in Example 1(A).

EXAMPLE 64*.

(A) 3-(a-phenylacetyl)-2-methylindole [11: R is CH R is C H CH CO; R isH] is prepared by reaction, in dry ether or tetrahydrofuran, ofphenylacetyl chloride with the Grignard reagent prepared from2-methylindole and methyl magnesium bromide using the proceduredescribed above in Example 1(A).

(B) a-[3 (a-phenylacetyl)-2-methyl 1 indole]acetic acid R1 is R2 is R3is R4 is H; Y is CH is prepared by reaction of ethyl bromoacetate with3-(wphenylacetyl)-2-methylindole in dry dimethylformamide in thepresence of sodium hydride, and saponification of the resulting ethyla-[3-(a-phenylacetyl)-2-methyl-1-indole]acetate all according to theprocedure described above in Example 1(B) and (C).

EXAMPLE 65 (A) 2-methyl-3-phenylindole [III R is CH R is C H R is H]..Amixture of 21.6 g. (0.2 mole) of phenylhydrazine, 26.8 g. (0.2 mole) ofphenylacetone, and 50 ml. of a solution of concentrated aqueoushydrochloric acid in 100 ml. of absolute ethanol, the whole dissolved in300 ml. of absolute ethanol, was refluxed on a steam bath for two hours,the mixture concentrated to a small volume in vacuo, and the resultinggreen sludge taken up in water/ether. The organic phase was washed twicewith water, and the resulting orange solution was dried and charcoaled.The pale yellow filtrate was taken to dryness in vacuo, and the residualyellow viscous gum distilled in vacuo at 0.5 mm., the product beingcollected at 143152 C. There was thus obtained 34 g. of2-methyl-3-phenylindole as a yellow viscous oil.

(B) Ethyl a-(2-methyl-3-phenyl-l-indole)acetate [I2 R1 is C2H5; R2 is R3is C6H5; R4 is Y is was prepared by reacting 33.6 g. (0.20 mole) ofethyl bromoacetate with 37 g. (0.18 mole) of 2-methyl-3- phenylindole inthe presence of 7.8g. (0.20 mole) of a 62% suspension of sodium hydridein mineral oil in 250 ml. of dimethylformamide using the proceduredescribed above in Example 1(B). There was thus obtainecl 47 g. of ethyla-(2-methyl-3-pheny1-1-indole)- acetate as a pale yellow oil.

(C) ot-(2-methyl-3-phenyl-l-indole)acetic acid [1: R is H; R is CH R isC H R is H; Y is CH was prepared by saponifying 47 g. (0.16 mole) ofethyl a-(2-methyl-3-phenyl-l-indole)acetate in a solution containing 400ml. of ethanol and ml. of 35% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallized from benzene giving 26 g. of a-(2-methyl-3-phenyl-1-indole)acetic acid, M.P. 159--67 C. (dec.).

Analysis calcd. for C H NO (percent): C, 76.96; H, 5.70; N, 5.28. Found(percent): C, 77.08; H, 5.67; N, 4.91.

In psychomotor activity studies in mice, a-(2-methyl-3-phenyl-1-indole)acetic acid was found to depress 74% of the motoractivity of the test animals at a dose of 300 mg./kg. (p.o.).Psychomotor depressant activity was determined in standard activitycages using the method of Dews, Brit. J. Pharmacol., 8, 46 (1953) inwhich mice, medicated with the test compound, are placed in wire meshcages equipped with a photoelectric cell so adjusted that a mousebreaking the beam activates a magnetic digital counter. Thus the numberof times the light beam is broken over a period of time is an indicationof the motor activity of the animals, and a reduction in the number ofcounts in the medicated mice over control groups, run simultaneously, istaken as evidence of psychomotor depressant activity. The dose at whichsuch reduction in motor activity was observed was recorded as the activedose.

EXAMPLE 66 (A) 3-(4 chlorophenyl) 2 methylindole [llz R is CH R is 4GIG- H R is H] was prepared by reacting 54 g. (0.5 mole) ofphenylhydrazine with 84 g. (0.5 mole) of a (4 chlorophenyl)-acetone in750 ml. of absolute ethanol and in the presence of 125 ml. ofconcentrated hydrochloric acid dissolved in 250 ml. of absolute ethanolusing the procedure described above in Example 65 (A). The crude productWas recrystallized from cyclohexane giving 97 g. of 3(4-chlorophenyl)-2-methylindole, M.P. 111.5 C. v

(B) Ethyl a [3 (4-chlor'ophenyl)-2-methyl-l-indole] acetate [1: R1 isC2H5; R2 is R3 is 4-CIC6H4; R4 is H; Y is CH was prepared by reacting 25g. (0.15 mole) of ethyl bromoacetate with 30 g. (0.12 mole) of3-(4-chlorophenyl) 2 methylindole in the presence of 5.8 g. (0.15 mole)ofv a 62% suspension of sodium hydride in mineral oil in 250 ml. ofdimethylformamide using the procedure described above in Example 1(B).There was thus obtained 45 g. of ethyl oc-[3-(4-Chl0l'0-phenyl-2-methyl-l-indole]acetate as a brown oil.

(C) a [3 (4 chlorophenyl)-Z-methyl-l-indole]acetic acid [1: R is H; R isCH R is 4-ClC H R is H; Y

is CH was prepared by saponification of 46 g. (0.14- mole) of ethyla-[3-(4-chlorophenyl)-2-methyl-1-indole] acetate in a solution of 400ml. of ethanol and ml. of 35% aqueous sodium hydroxide using theprocedure described above in Example 1(C). The crude product wasrecrystallizedtwice from ethanol giving 11.0 g. .of (at-[3-(4-chlorophenyl) 2 methyl 1 indole]acetic acid, M.P. 188-202 C. (dec.).AnaIysis..-Calcd. for C H CINO (percent): C, 68.11; H, 4.71; N, 4.67;01, 11.8 3. Found'(percent): c, 68.24; H, 4.76; N, 4.62; CI, 11.61.

29 EXAMPLE 67 (A) Ethyl e (3 phenyl 2 methyl-1-indole)pr'o pionate [Iz Ris C H R is ..C H R is C H R is H; Y is CH CH was prepared by reacting33 g'. (0.20 mole) of ethyl S-bromopropionate with 31.4 g. (0.15 mole)of 3 phenyl 2 methylindole in the presence of 7.1 g. (0.18 mole) ofa 62%suspensionof sodium hydride in mineral oilin 250ml. ofdimethylformarnide using the manipulative procedure described above inExample 1(B). There was thus obtained 46 g. of ethyl B-(3; phenyl 2methyl 1 indole)propionate as a yellow oil.

(B) 3(3-phenyl 2 methyl 1 ind0le)propioni c acid [II R1 iS H; R2 iS CH3;R3 iS C6H5; R4 iS Y is was prepared by saponification of 46 g..(0.2 7mole) of ethyl 8 (3 phenyl 2 methyl-1-indole)propionate in i a solutionof 500 ml. of ethanol and 160 ml. of 10% aqueous sodium hydroxide usingthe procedure described above in Example 1C. The crudeproduct wasrecrystallized from ethanol/water giving 21 g. of ,8-(3 phenyl-2-methyl-l-indole)propionic acid, M.-P. 135137.5' C.

Analysis-Called. for C H N (percent): C; 77:39; A,

H, 6.13; N, 5.01. Found (percent): C, 77.75; H, 6.28; N, 4.87. I I p 5(3 phenyl 2 methyl 1 indole)propionic acid,

when tested as a psychomotor depressant as described above in example 65(C), was found to depress 75% of the motor activity of the test animalsat a dose of 300'mg./ k g (D0):

EXAMPLE I68 (A) Ethyl [5' [3 (4-ch1orophenyl) 2-methylel-indolejpropionate [1: R is C H R is CH R is 4-ClC H R is H; Y is CH CH wasprepared by reacting g. (0.083 mole) of 3 (4chlorophenyl)-2-methylindole with*16.5 g. (0.091 mole) of ethyl18-bromopropionate in 150- ml. of dry ,dimethylformamide in the.presenceof 3.62 g. (0.092 mole) of a 61% suspension ofi sodium hydride:in mineral oil using the procedure. described above airriExample 1(B).There was thus obtained .ethyl B -f,[-3 (4-.chlorophenyl)-2-methyl-1-indole]propionate.

- B-[3-(4-chlorophenyl 2 methyl-l-indole]propionic acid [I: R is H; R isCH R is 4-ClC H -y-R- is H;'=Y is CH CH was prepared by saponificationof the ethyl ,8-[3- (4-chlorophenyl) 2 methyl 1 indolelpropionateob.-tained above in Example 68 (A) in a solution containing 30 g. ofpotassium hydroxide dissolved in 200 ml. of methanol using the proceduredescribed" above in' Example 1(C). The crude product wasrecrystallized-"from belizene giving 8.4 g. of B-[3-(4-chlorophenyl) 2methyl 1 hydrazine in ethanol in the presence of hydrochloric acid usingthe procedure described-above in Exarr'1ple'65 (A).

' water. The two solutions were then combined, taken. to

R is 6 CH S; Y is CH all according to the procedure described above inExample 1(B) and(C).

EXAMPLE 70 1 (A) 3. (3,4 methylenedioxyphenyl) 2 hydroxymethyl 6methylmercaptoindole [II: R is CH OH; R3 iS 3,4-6T3HFC6H3 R is 6-CH S]is prepared by reduction of 3-(3,4-methyl- 5,enedioxyphenyl)-2-carbethoxy 6 methylmercaptoindole with lithiumaluminum hydride in refluxing tetrahydrofuran, and isolation of theproduct, after decomposition of the resulting complex and unreactedhydride with water.

(B) a [3 (3,4-methylenedioxyphenyl)-2-hydroxymethyl 6methylmercapto-l-indole] acetic acid [1: R is H; R is CH OH; R is 3,46CHzO CGIIg R; is 6-CH S; Y is CH is prepared by reaction of ethylbromoacetate with 3 (3,4-methylenedioxyphenyl)2-hydroxymethyl 6methylmercaptoindole in dry dimethylformamide in the presence of sodiumhydride, and saponification of the resulting ethyl or [3(3,4-methylenedioxyphenyl) 2hydroxymethyl-6-methylmercapto-l-indol'e]acetate all according to theprocedure described above in Example 1(B) and (C).

EXAMPLE 71 (A) 3 benzyl 2 methylindole [II: R is CH R is Q H CH R is H]is prepared by reacting 2-phenylethyl methyl ketone with phenylhydrazinein ethanol in the presence of hydrochloric acid using the proceduredescribed above in Example 65 (A).

(B) a (3 benzyl-Z-methyl-l-indole)acetic acid [1: R is H; R is CH R is CH CH R is H; Y is CH I is prepared by reacting ethyl bromoacetate with3-benzyl-2- methylindole in dry dimethylformamide in the presence sodiumhydride, and saponification of the resulting ethyl ix (3benzyl-Z-methyl-l-indole)acetate all according to the proceduredescribed above in Example 1(B) and (C).

EXAMPLE 72 (A). 3-(4-chlorobenzyl)-2-methyllindole [II: R is CH R is4-ClC H CH R is H. ].-In two separate runs, 25 g. (0.093 mole) and 40 g.(0.15 mole) of 3-(4-chlorobenzyl)-2-methylindole, dissolved in 250 ml.and 35-0 ml. portions, respectively, of tetrahydrofuranwas added in.eachcase to a solution containing 0.25 mole of di- ,borane, in 250 ml. oftetrahydrofuran. The reaction mix tures were refluxed in each case forone and one-half hours, cooled to room temperature, and the excessdibore destroyed by the addition of a small amount of dryness in vacuo,the residual material taken upin about 1.5 liters. of ethyl acetate, theorganic solution washed with water, then with brine, dried, and taken todryness giving-6 4 g.-.of 3-(4-chlorobenzyl)-2-methylindole.

(B) on [3 (3,4-methylenedioxyphenyl)-2-ca'rboxy fication of theresulting ethyl t-[3-(3,4-methylenedioxyethyl phenyl) 2carbethoxy-6-methylmercapto-l-indole] acetate R is C2H5; R2 is R3 =iS(B) Ethyl a-[3-(4 --chlorobenzyl)-2-methyl-1-indole] acetate [1: R is CH R is CH R is 4-ClC H CH R is H; Y is CH was prepared 'by reaction of18.4 g. (0.11 mole) of 3-(4-chlorobenzyl)-2-methylindole in the presenceof 5.1 g. (0.11 mole) of a 52% suspension of sodium hydride-in mineraloil in 250' ml. of dry dimethylformamide using the procedure describedabove in- Example 1(B). There was thus obtained 30 g. of ethyl (Di-[3 (4chlorobenzyl)-2-methyl-1-indole-]acetic acidasared-brown oil. A '(C)a-['3-(4-chlorobenzyl)-2 methyl-l-in'dole1acetic R1 iS R2 is R34-ClC6H4CH2; R4 H; Y is CH was prepared by saponification of 30 g.(0.088 mole) of ethyl u-[3-'(4-chlorobenzyl)-2-methyl 1- 31indole]acetate in a solution of 800 ml. of ethanol and 200 ml. ofaqueous sodium hydroxide using the procedure described above in Example1(C). The crude product was recrystallized from benzene giving 7.3 g. ofa-[3-(4-chlorobenzyD-2 methyl-1-indole]acetic acid, M.P. 202-205 C.

Analysis.Calcd. for C H ClNO (percent): C,

68.89; H, 5.14; N, 4.46; Cl, 11.30. Found (percent):

C, 69.02; H, 5.20; N, 4.42; Cl, 11.49.

EXAMPLE 73 Sodium B (3-benzoyl-2-methyl-l-indole) propionate [II R1 isNa R2 is R3 is R4 is Y is CH CH Seven grams (0.023 'mole) offi-(3-benzoyl- 2-methyl-1-indole)propionic acid were dissolved in theminimum amount of dimethylformamide, the pH of the solution was adjustedto 10 with 10/ aqueous sodium hydroxide, the mixture was warmed to 50 C.and diluted with 100 ml. of hot water. On cooling, the product separatedas a crystalline solid which was collected, washed with water, then withacetone and recrystallized from methanol/acetone to give 3.6 g. ofsodium ,6-(3- benzoyl-2-methyll-indole propionate.

EXAMPLE 74 R is H; Y is CH is prepared by reacting ethyl bromoacetatewith 2-methyl-3-(3-phenyl-3-oxo-l propenyl)indole in drydimethyl-formamide in the presence of sodium hydride, and saponificationof the resulting ethyl a-[3-(3-phenyl-3-oxo-l-propenyl)-2-rnethyl 1indole] acetate all according to the procedure described above inExample 1(B) afid';(C).

EXAMPLE 75 fi-[3-(4-acetylaminobenzoyl)-2-methyl-1 indo1e]propionic acid[1; R is H; R is CH R is 4-CH CONHC H CO R is H; Y is CH CH ].--Amixture of 6.3 g. (0.018 mole) of ethylfl-[3-(4-aminobenzoyl)-2-methyl-1-indole] propionate and 25 ml. ofacetic anhydride was warmed to 60 C. on a steam bath. The mixture, whichdeposited a copious precipitate, was treated with water, heated toreflux, cooled, and the solid which separated was collected and washedwith water to give 11 g. of a cream colored solid. The latter wasrecrystallibed from ethanl to give 6.0 g. of ethylfl-[3-(4-acetylaminobenzoyl)-2- methyl-l indole]propionate, M.P.188-190" C. The latter was saponified in sodium hydroxide using theprocedure described above in Example 1(C), and the crude productrecrystallized from acetonitrile to give5-[3-(4-acetylaminobenzoyl)-2-methyl 1 indole] propionic acid, M.P. 215-2l8 C.

EXAMPLE 76 a-(3-benzoyl-2-methyl-4,5,6,7-tetrahydro L l indole) aceticacid [Ia: R is H; R is CH R is C H CO; R; is H; Y is CH ].-Reaction of2-(2-oxopropyl)cyclo hexanone with glycine in glacial acetic acid atroom temsaponification using the procedure described above in Example1(C) affords a-(3-benzoyl-2-methyl-4,5,6,7- tetrahydrol-indole) aceticacid.

EXAMPLE 77 13 (3 -benzoyl-2-methyl-4,5,6,7-tetrahydro 1 indole)propionic acid [Iaz R is H; R is CH R is C H CO; R is H; Y' is CH CH isprepared by reaction of 2- (2-oxo-1-propyl)cyclohexanone with a-alanineis glacial citacetic acid; esterification with ethanol in the presenceof sulfuric acid and reaction of the resulting ethyl B-(2-methyl-4,5,6,7-tetrahydro-l indo1e)propionate with benzoyl chlorideinthe presence of stannic chloride or boron trifiuoride; andsaponification of the resulting ethylS-(3-benzoy1-2-methyl-4,5,6,7-tetrahydro-1 indole)propionate allaccording to the procedure described above in Example 76.

EXAMPLE 78 a-[3-(4-chlorobenzoyl)-2-methyl-4,5,6,7tetrahydro-lindole]-acetic acid [Iaz R is H; R; is CH R is 4-c1c,H.co

R is H; Y is CH is prepared by reaction of ethyl bromo acetate with theethyl u-(2-methyl-4,5,6,7-tetrahydro-lindole)acetate described above inExample 76 in the presence of stannic chloride or boron trifiuorideusing the procedure described above in Example 76, and saponification ofthe resulting ethyl a-[3-(4-chlorobenzoyl)-2-methyl-4,5,6,7-tetrahydro-l-indole]acetate using the procedure describedabove'in Example 1(C).

EXAMPLE 79 Ethyl {3-[3-(4-chlorobenz0yl) 2methyl-4,5,6,7-tetrahydro-l-indole]propionic acid [Ia: R is H; R is CH Ris 4-CIC H CO'; R is H; Y is CH CH is prepared by reacting4-chlorobenz0yl chloride with the ethyl fl-(Z- methy1-4,5,6,7 tetrahydro1 indole)propionate described above in Example 77 in the presence ofstannic chloride or boron trifiuoride using the procedure describedabove in Example 76; and saponification of the resulting ethylB-[3-(4-chlorobenzoyl)-2-methyl-4,5,6,7 tetrahydro-1-indole]propionateusing the procedure described above in Example 1(C).

EXAMPLE s0 'u-[3-(4-methylbenzoyl)-2-methy1 4,5,6,7 tetrahydro1-indole]acetic acid [Ia: R is H; R is CH R is 4-CH C H CO; R is H; Y isCH is prepared by reaction of 4-methylbenzoyl chloride with the ethyla-(Z-methyl- 4,5,6,7-tetrahydro-l-indole)acetate described above inExample 76 in the presence of stannic chloride or boron trifiuorideusing the procedure described above in Exa'mple 76; and saponificationof the resulting ethyl 06-[3- (4-methylbenzoylj-2-methyl 4,5,6,7tetrahydro-l-indole]propionate using the procedure described above inExample 1(C).

EXAMPLE 81 Ethyl B-[3-(4-methylbenzoyl) 2 methyl 4,5,6,7-tetrahydro-l-indoleJpropionic acid [Iaz R is H; R is CH3; R3 is4-CH3CGH4CO; R4 is Y is iS prepared byreaction of 4-chlorobenzoylchloride with the ethyl fi-(Z-methyl 4,5,6,7tetrahydro-1-indole)propionate described above in Example 77 in thepresence of stannic chloride or boron trifiuoride using the proceduredescribed above in Example 76; and saponification of the resulting ethylB-[3-(4-methylbenzoyl) 2 methyl 4,5, 6,7-tetrahydro-1-indole]propionateusing the procedure described above in Example 1(C).

EXAMPLE 82 'y-(3-benZoyl-2-methyl l indole)-butyric acid [I: R is R2 isR3 is R4 is Y is was prepared by reaction of 9.6 g. (0.05 mole) of ethyl'y-brornobutyrate with 11 g. (0.05 mole) of 3-benzoyl-2- EXAMPLE 83'y-[3(2-furoyl)-2-methyl-6-acetoxy 1 indolelbutyric acid [II R1 is R2 isR3 is 2-C4H3O-CO; R4 is 6CH COO; Y is (CH is prepared by reaction of v-[3-(2-furoyl)-2-methyl 6 hydroxy 1 indoleJbutyric acid with aceticanhydride in the presence of pyridine.

EXAMPLE 84 a-[3-(3,4-methylenedioxyphenyl)-2-carboxy 6methylsulfinyl-l-indole]acetic acid [1: R is H; R is COOH; R is 33,4-001-113315? R is 6-CH SO; Y is CH is prepared by reaction ofa-[3-(3,4-methylenedioxyphenyl)-2-carboxy 6methylmercapto-1-indole1acetic acid with 1 mole of hydrogen peroxide inglacial acetic acid at room temperature.

EXAMPLE 85 a-[3-(3,4-methylenedioxyphenyl)-2-carboxy 6methylsulfonyl-l-indole]acetic acid [I: R is H; R is COOH; R is 3 3,4oCHzO C l-I R is 6-CH SO' Y is CH is prepared by reaction ofa-[3-(3,4-methylenedioxyphenyl)-2-carboxy 6methylmercapto-1-indole]acetic acid with 2 moles of hydrogen peroxide inglacial acetic acid at room temperature.

EXAMPLE 86 w-[3-(4-methoxybenzoyl)-2-methyl 1 indole]hep tanoic acid [1:R is H; R is CH R is 4-CH OC H CO; R is H; Y is (CH is prepared byreaction of ethyl bromoheptoate with 3-(4-methoxybenzoyl)-2-methylindolein dry dimethylformamide in the presence of sodium hydride, andsaponification of the resulting ethyl w-[3- (4-methoxybenzoyl)-2-methyl1 indoleJheptoate with alcoholic alkali all according to the proceduredescribed above in Example 1(B) and (C).

EXAMPLE 87 (A) 3-(3,4,5 trimethoxyphenyl)-2-methylind0le [II: R2 is R3is 3,4,5-(CH O) C H R4 is is prepared by reacting phenylhydrazine withmethyl 3,4,5-trimethoxy- 34 benzyl ketone in the presence of mineralacid using the procedure described above in Example (A).

(B) fi-[3-(3,4,5-trimethoxyphenyl) 2 methyl-l-indole]propionic acid [I:R is H; R is CH R is 3,4,5- (CH O) C H R is H; Y is CH CH is prepared byreaction of ethyl B-bromopropionate with 3-(3,4,5trimethoxyphenyl)-2-methylindole in dry dime'thylformamide in thepresence of sodium hydride, and saponification in alcoholic alkali ofthe crude ethyl B-[3-(3,4,5-trimethoxyphenyl) 2methyl-1-indole1propionate thus produced all according to the proceduredescribed above in Example 1(B) and (C).

EXAMPLE 88 fl-(3-phenyl 2 methyl 4,5,6,7 tetrahydro-l-indole) propionicacid [Iaz R is H; R is CH R is C H R is H; Y is CH CH is prepared byrefluxing, under a Dean- Stark trap, a benzene solution of cyclohexanoneand pyrrolidine; reaction of the resulting cyclohexanonepyrrolidineenamine with a-bromo-a-phenylacetone in refluxing methanol followed byhydrolysis with water; and reaction of the resulting2-(l-phenyl-Z-oxopropyl)cyclohexanone with glycine using the proceduredescribed above in Example 76.

I claim:

1. A compound having the formula:

lit

Noller: Chemistry of Organic Compounds (1965), p. 183.

Sumpter et al.: The Chemistry of Heterocyclic Compounds (Indole &Carbazole Systems) (1954), pp. 44-45.

ALEX MAZEL, Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl.X.R.

232 1 33 UNITED 51111155 lnl'rrlhil 011 11013 CERTIFICATE OF CORRECTIONPatent 3,557,142 I Dated January 19, 1971 Inventor (5) Malcolm H. BellPAGE 1 It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown be] ow:

r- Column 1, line 68, "alkanyl" should read -alk anoyl--.

Column 2, line 12, "interceptor" should read "acceptor-- line 52, "R-benzy1" should read --R -benzy1--.

Column 3, line 68, "of basic" should \read --of a basic--. Column'5,line 8, "later" should read --latter--.

Column 8, line 6, "acetatic" should read --acet1c--. Column 9, line 38,"acetate acid" should read "acetic ac Column 10, line 51,1-[3,4-d1ch1orobenzoyl). "should r1 --a-[B-(BJL-dichlorobenzoyl)...--.

Column 11, line 68, "M.P. 226-2295 c. should read --M.P 226-229.5C.--.

Column 12, line '48, "anti-vacterial" should read --antlbacterial--.

Column 1 lines 15-16, "E-benzolindole" should read "3- benzoy1lndo1e--;line 53, 0.068" should read --(0.068--.

Column 1 1, llne 61, "189-190V. should read "139-19190. line 63, "C,66.23; should read --C, 68.25;".

Column 16, line 2, "hydrxide" should read --hydroxlde--.

Column 17, line 10, "B-bromopropionate" should read --B-bromoprop1onate--.

Column 19, line 67, "c, 17.20; should read --c, 1.20;") I.

( 7 l q 1 u 1" CERTIFiC/l'i'h O COHBEUHON Patent No. 1, 551,142 DatedJanuary 19 1971 PAGE 2 1m entor(s) Malcolm H. Bell It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrcc ted as shown below:

I." Column 21, line 38, "65.6 g. should read --65.5 g. li 46,(2,6-dichlorobenzoyl-E-methyl. should read (2,dichlorobenzoyl)-2-methyl. line & [R is H; should read [1: R is H;

Column 23, line 7, -2-methyl-l-indolg-" should read-2-methyl-l-lndole]-- line 32, delete- A)"; line 49, dryness should read-to dryness--.

Column 24, line 56, "palladium-on-channel" should read-palladium-on-charcoa1--; line 65, before "Y is CH insert --R, is H;--.

Column 25, line 10, "procedcre" should read --procedure-- line 18,.-2-mtthy1-l-. should read -2-methyl-l-. line 39, "R is CH Co; shouldread "R is C H CO;--r

Column 26, line with Grignard" should read --with the Grignard--; line1- 4, is l-C H N-CO; should read is L c H NO-CO;--; lines 71- 2 "dlmtylformanide" should re d --d mt ylformamide line 7i, "s1 1" should read---all--.

Column 27, line 10, "recation" should read --react1on--.

Column 28, line 62, 'phenyl-2-" should read --phenyl)-2-- Column 30,line 45 "methyllindole" should read -methylindole--; lines 47-48,(M-chlorobenzyl)" should read "(4- chlorobenzoyl)---; lines 54-55,"dibore" should read --diborane Column 31, line 13, "[I: R is Na" shouldread [1: R Na;--; line 17, "with 10/" should read --w1th 10%; line 56,crystallibed" should read --recrystallized--; line 56, "ethanl shouldread --ethanol--.

" UNITED slums minim OFFICE Patent 3,557,142 Dare-d January 19. 1971Inventor(s) Malcolm H. Bell PAGE 3 It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 32, line 8, "oz-alanine" should read --B-a1anine--; line 9,"citacetic acid" should read --acetic acid--.

Signed and sealed this 18th day of January 1972.

(SEAL) Attest:

ROBERT GOTTSCHALK EDWARD M.F'LETCHER JR.

, Acting Commissioner of Patent Attestin Officer

